7TM Receptors

Authors

  • S P H Alexander,

  • A Mathie,

  • J A Peters


7TM Receptors

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Overview: Alongside the 7-transmembrane receptors listed in the Guide to Receptors and Channels, IUPHAR recognises a number of genes, which sequence analysis suggests code for 7-transmembrane receptors and for which an endogenous ligand has yet to be identified (Foord et al., 2006).

Below are listed a number of these genes, for which preliminary evidence for an endogenous ligand has been published.

Gene Symbol (Ensembl ID)Putative endogenous ligandComment
GPR17 (ENSG00000144230)Dual leukotriene and UDP (Ciana et al., 2006)Also known as R12
GPR18 (ENSG00000125245)N-Arachidonoylglycine, cannabinoid-like (Kohno et al., 2006) 
GPR34 (ENSG00000171659)Lysophosphatidylserine (Sugo et al., 2006) 
GPR35 (ENSG00000178623)Kynurenic acid (Wang et al., 2006)Has also been reported to respond to the phosphodiesterase inhibitor zaprinast (Taniguchi et al., 2006)
GPR37 (ENSG00000170775)Head activator (Rezgaoui et al., 2006)Also known as PAELR, EDNRLB
GPR39 (ENSG00000183840)Obestatin (Zhang et al., 2005) or Zn2+ (Holst et al., 2007) 
GPR55 (ENSG00000135898)Cannabinoid-like (Baker et al., 2006) 
GPR119 (ENSG00000147262)N-Oleoylethanolamine (Overton et al., 2006) 
GPR120 (ENSG00000186188)Free fatty acids (Katsuma et al., 2005; Hirasawa et al., 2005) 
MRGPRD (ENSG00000172938)β-Alanine (Shinohara et al., 2004)Also known as TGR7; potentially exists as a heteromer with MRGPRE (GPR167, ENSG00000184350) (Milasta et al., 2006)
MRGPRX1 (ENSG00000170255)BAM8-22 (Chen and Ikeda, 2004)Also known as SNSR4
MRGPRX2 (ENSG00000183695)PAMP (Kamohara et al., 2005), cortistatin (Robas et al., 2003) 
OXGR1 (ENSG00000165621)α-Ketoglutarate (He et al., 2004)Also known as GPR80, GPR99, P2Y15; Initially proposed to be a receptor for nucleotides
SUCNR1 (ENSG00000198829)Succinate (He et al., 2004)Also known as GPR91

Further Reading

Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP et al. (2005). International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol Rev57: 279–288.

References

Baker D et al. (2006). Trends Pharmacol Sci27: 1–4.

Chen H, Ikeda SR (2004). J Neurosci24: 5044–5053.

Ciana P et al. (2006). EMBO J25: 4615–4627.

He W et al. (2004). Nature429: 188–193.

Hirasawa A et al. (2005). Nat Med11: 90–94.

Holst B et al. (2007). Endocrinology148: 13–20.

Kamohara M et al. (2005). Biochem Biophys Res Commun330: 1146–1152.

Katsuma S et al. (2005). J Biol Chem280: 19507–19515.

Kohno M et al. (2006). Biochem Biophys Res Commun347: 827–832.

Milasta S et al. (2006). Mol Pharmacol69: 479–491.

Overton HA et al. (2006). Cell Metab3: 167–175.

Rezgaoui M et al. (2006). J Cell Sci119: 542–549.

Robas N et al. (2003). J Biol Chem278: 44400–44404.

Shinohara T et al. (2004). J Biol Chem279: 23559–23564.

Sugo T et al. (2006). Biochem Biophys Res Commun341: 1078–1087.

Taniguchi Y et al. (2006). FEBS Lett580: 5003–5008.

Wang J et al. (2006). J Biol Chem281: 22021–22028.

Zhang JV et al. (2005). Science310: 996–999.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Additional ‘orphan’ 7-transmembrane receptors

In the table below, putative 7-transmembrane receptors with as-yet unidentified endogenous ligands have been listed.

SymbolEnsembl IDOther namesSymbolEnsembl IDOther names
GPR1ENSG00000183671 GPR115ENSG00000153294FLJ38076, PGR18
GPR3ENSG00000181773ACCAGPR116ENSG00000069122DKFZp564O1923, KIAA0758
GPR4ENSG00000177464Proton-sensing, sphingosylphosphorylcholineGPR123ENSG00000197177KIAA1828
   GPR124ENSG00000020181Tumour endothelial marker 5
GPR6ENSG00000146360 GPR126ENSG00000112414FLJ14937
GPR10ENSG00000119973 GPR127ENSG00000186629PGR16, EMR4
GPR12ENSG00000132975GPCR21GPR128ENSG00000144820FLJ14454
GPR15ENSG00000154165 GPR132ENSG00000183484G2A
GPR19ENSG00000183150 GPR133ENSG00000111452PGR25
GPR20ENSG00000204882 GPR136ENSG00000124818OPN5, neuropsin, PGR14
GPR21ENSG00000188394 GPR137ENSG00000173264GPR137A, TM7SF1L1
GPR22ENSG00000172209 GPR139ENSG00000180269PGR3
GPR25ENSG00000170128 GPR140ENSG00000172935MRGPRF, GPR168, RTA
GPR26ENSG00000154478 GPR141ENSG00000187037PGR13
GPR27ENSG00000170837SREB1GPR142ENSG00000196169PGR2, KIF19
GPR31ENSG00000120436 GPR143ENSG00000101850OA1
GPR32ENSG00000142511 GPR144ENSG00000180264PGR24
GPR33ENSMUSG00000035148Pseudogene in manGPR146ENSG00000164849PGR8
GPR37ENSG00000170775PAELR, EDNRLBGPR148ENSG00000173302PGR6, brain and testis restricted GPCR
GPR45ENSG00000135973PSP24   
GPR48ENSG00000205213Leucine-rich repeat-containing G-protein coupled receptor 4GPR149ENSG00000174948PGR10, IEDA
   GPR150ENSG00000178015PGR11
GPR49ENSG00000139292LGR5, GPR67, FEX, HG38, MGC117008GPR151ENSG00000173250PGR7, GALR4, GPCR-2037
   GPR152ENSG00000175514PGR5
GPR50ENSG00000102195H9GPR153ENSG00000158292PGR1
GPR52ENSG00000203737 GPR154ENSG00000187258NPS1, PGR14, GPRA
GPR56ENSG00000205336TM7LN4, TM7XN1GPR155ENSG00000163328DEPDC3, DEP.7, FLJ31819, PGR22
GPR61ENSG00000156097BALGR   
GPR62ENSG00000180929 GPR156ENSG00000175697PGR28, GABABL
GPR63ENSG00000112218PSP24BGPR157ENSG00000180758FLJ12132
GPR64ENSG00000173698HE6GPR158ENSG00000151025KIAA1136
GPR65ENSG00000140030TDAG8GPR160ENSG00000173890GPCR150, GPCR1
GPR68ENSG00000119714OGR1, Proton-sensingGPR161ENSG00000143147RE2
GPR70ENSG00000173662TAS1R1GPR162ENSG00000110811A-2, GRCA
GPR71ENSG00000179002TAS1R2GPR164ENSG00000180785Olfactory receptor 51E1, prostate overexpressed G protein-coupled receptor
GPR72ENSG00000123901GPR83   
GPR75ENSG00000119737WI31133   
GPR77ENSG00000134830C5L2GPR165ENSMUSG00000031210 
GPR78ENSG00000155269 GPR169ENSG00000182170Mas-related GPR, member G
GPR81ENSG00000196917TAGPCR, GPR104GPR171ENSG00000174946H963
GPR82ENSG00000171657 GPR172AENSG00000185803PAR1, Porcine endogenous retrovirus A receptor 1
GPR84ENSG00000139572EX33   
GPR85ENSG00000164604SREB2GPR173ENSG00000184194Super conserved receptor expressed in brain 3
GPR87ENSG00000138271GPR95   
GPR88ENSG00000181656STRGGPR174ENSG00000147138FKSG79
GPR90ENSMUSG00000059408Mas-related GPR, member HGPR175ENSG00000163870TPRA40
GPR97ENSG00000182885Pb99, PGR26GPR176ENSG00000166073Gm1012, HB954
GPR98ENSG00000164199VLGR1GPR177ENSG00000116729Protein wntless homolog, putative NFkB-activating protein 373
GPR101ENSG00000165370    
GPR107ENSG00000148358KIAA1624, RP11-88G17, FLJ20998, LUSTR1GPR178ENSG00000146433KIAA1423, TMEM181
   GPR179ENSG00000188888GPR158L1
GPR110ENSG00000153292hGPCR36, PGR19GPR180ENSG00000152749Intimal thickness-related receptor
GPR111ENSG00000164393hGPCR35, PGR20   
GPR112ENSG00000156920RP1-299I16, PGR17EBI2ENSG00000169508Epstein-Barr virus induced gene 2, lymphocyte-specific G protein-coupled receptor
GPR113ENSG00000173567hGPCR37, PGR23   
GPR114ENSG00000159618PGR27   

5-HT (5-Hydroxytryptamine)

5-HT receptors [nomenclature as agreed by NC-IUPHAR Subcommittee on 5-HT receptors (Hoyer et al., 1994) and subsequently revised (Hartig et al., 1996)] are, with the exception of the ionotropic 5-HT3 class, 7TM receptors where the endogenous agonist is 5-HT. The diversity of 5-HT receptors is increased by alternative splicing that produces isoforms of the 5-HT2A (non-functional), 5-HT2C (non-functional), 5-HT4, 5-HT6 (non-functional) and 5-HT7 receptors. RNA editing produces 5-HT2C receptor isoforms that differ in function, such as efficiency and specificity of coupling to Gq/11 (reviewed by Sanders-Bush et al., 2003; Bockaert et al., 2006).

Nomenclature5-HT1A5-HT1B5-HT1D5-ht1E
Other names5-HT1Dβ5-HT1Dα
Ensembl IDENSG00000178394ENSG00000135321ENSG00000179546ENSG00000168830
Principal transductionGi/oGi/oGi/oGi/o
Selective agonists (pKi)8-OH-DPAT (8.4-9.4), U92016A (9.7)Sumatriptan (6.5-8.1) eletriptan (8.0), L694247 (9.2)PNU109291 (9.0—gorilla, Ennis et al., 1998) sumatriptan (8.0-8.7), eletriptan (8.9), L694247 (9.0, Wurch et al., 1998)
Selective antagonists (pKi)(±)WAY100635 (7.9-9.2), (S)-UH301 (7.9-8.6), NAD299 (robalzotan, 9.2)SB236057 (8.2, inverse agonist, Middelmiss et al., 1999), SB224289 (inverse agonist, 8.2-8.6), GR55562 (pKB 7.4, Hoyer et al., 2002)SB714786 (9.1) BRL15572 (7.9)
Probes (KD)[3H]WAY100635 (0.3 nM, Khawaja et al., 1997), [3H]NAD299 (0.16 nM), [3H]8-OH-DPAT (0.4 nM), [11C]WAY100635 (PET ligand), p-[18F]MPPF (PET ligand)[3H]Alniditan (2.0-2.4 nM) [3H]eletriptan (3 nM), [3H]sumatriptan (11 nM) [125I]GTI, [3H]GR125743 (2.6 nM, Xie et al., 1999)[3H]Alniditan (1.2-1.4 nM) [3H]eletriptan (0.9 nM), [3H]sumatriptan (7 nM), [125I]GTI, [3H]GR125743 (2.8 nM, Xie et al., 1999)[3H]5-HT (6 nM)
Nomenclature5-HT1F5-HT2A5-HT2B5-HT2C
Other names5-HT1Eβ, 5-HT6D, 5-HT25-HT2F5-HT1C
Ensembl IDENSG00000179097ENSG00000102468ENSG00000135914ENSG00000147246
Principal transductionGi/oGq/11Gq/11Gq/11
Selective agonists (pKi)LY344864 (8.2, Phebus et al., 1997) LY334370 (8.7)DOI (7.4-9.2)DOI (7.6-7.7), Ro600175 (8.3), BW723C86 (7.3-8.6)DOI (7.2-8.6), Ro600175 (7.7-8.2) WAY163909 (8.0, Dunlop et al., 2005)
Selective antagonists (pKi)ketanserin (8.1-9.7), MDL100907 (9.4)RS127445 (9.0), EGIS-7625 (9.0)SB242084 (8.2-9.0), RS102221 (8.3-8.4)
Probes (KD)[3H]LY334370 (0.5 nM), [125I]LSD[3H]ketanserin (0.2-1.3 nM), [3H]RP62203 (fananserin, 0.13 nM—rat, Malgouris et al., 1993), [11C]M100907 (PET ligand), [18F]altanserin (PET ligand)[3H]5-HT (8 nM—rat)[3H]mesulergine (0.5-2.2 nM), [3H]LSD
Nomenclature5-HT45-ht5A5-ht5B5-HT6
Other names5-HT5α
Ensembl IDENSG00000164270ENSG00000157219ENSMUSG00000050534ENSG00000158748
Principal transductionGsGi/Go?None identifiedGs
Selective agonists (pKi)BIMU8 (7.3), ML10302 (7.9-9.0), RS67506 (8.8-guinea-pig, Eglen et al., 1995)
Selective antagonists (pKi)GR113808 (9.3-10.3), SB204070 (9.8-10.4), RS100235 (8.7-12.2)SB699551 (8.2)SB271046 (8.9), SB357134 (8.5, Bromidge et al., 2001), Ro630563 (7.9-8.4)
Probes (KD)[3H]GR113808 (50-200 pM), [125I]SB207710 (86 pM—piglet, Brown et al., 1993), [3H]RS57639 (0.25 nM-guinea-pig, Bonhaus et al., 1997)[3H]5-CT (2.5 nM), [125I]LSD (0.2 nM)[3H]5-CT, [125I]LSD[125I]SB2585 (1.0 nM, Hirst et al., 2000), [3H]Ro630563 (5 nM, Boess et al., 1998), [3H]5-CT, [125I]LSD (2 nM)
Nomenclature5-HT7
Other names5-HTX, 5-HT1-like
Ensembl IDENSG00000148680
Principal transductionGs
Selective agonists
Selective antagonists (pKi)SB656104 (8.7, Forbes et al., 2002), SB269970 (8.6-8.9 Thomas et al., 2000), SB258719 (7.5)
Radioligands (KD)[3H]SB269970 (1.2 nM, Thomas et al. 2000), [3H]5-CT (0.4 nM, Thomas et al., 2000) [3H]LSD (3 nM), [3H]5-HT (1-8 nM)

Tabulated pKi and KD values refer to binding to human 5-HT receptors unless indicated otherwise. Unreferenced values are extracted from the NC-IUPHAR database (http://www.iuphar-db.org). The nomenclature of 5-HT1B/5-HT1D receptors has been revised (Hartig et al., 1996). Only the non-rodent form of the receptor was previously called 5-HT1Dβ: The human 5-HT1B receptor (tabulated) displays a different pharmacology to the rodent forms of the receptor due to Thr335 of the human sequence being replaced by Asn in rodent receptors. NAS181 is a selective antagonist of the rodent 5-HT1B receptor. Fananserin and ketanserin bind with high affinity to dopamine D4 and histamine H1 receptors respectively, in addition to 5-HT2A receptors. The human 5-ht5A receptor has been claimed to couple to several signal transduction pathways when stably expressed in C6 glioma cells (Noda et al., 2003). The human orthologue of the mouse 5-ht5B receptor is non-functional due to interruption of the gene by stop codons. In addition to the receptors listed in the table, an ‘orphan’ receptor, unofficially termed 5-HT1P, has been described (Gershon, 1999).

Abbreviations: 5-CT, 5-carboxamidotryptamine; 8-OH-DPAT, 8-hydroxy-2-(di-n-propylamino)tetralin; BIMU8, (endo-N-8-methyl-8-azabi-cyclo[3.2.1]oct-3-yl)-2,3-dihydro-3-isopropyl-2-oxo-1H-benzimidazol-1-carboxamide hydrochloride; BRL15572, 3-[4-(3-chlorophenyl) piperazin-1-yl]-1,1,-diphenyl-2-propanol; BW723C86, 1-[5(2-thienylmethoxy)-1H-3-indolyl]propan-2-amine hydrochloride; EGIS-7625, 1-benzyl-4-[(2-nitro-4-methyl-5-amino)-phenyl]-piperazine; GR55562, 3-[3-(dimethylamino)propyl]-4-hydroxy-N-[4-(4-pyridinyl)phenyl]benzamide; GR113808, [1-2[(methylsuphonyl)amino]ethyl]-4-piperidinyl]methyl-1-methyl-1H-indole-3-carboxylate; GR125743,n-[4-methoxy-3-(4-methyl-1-piperizinyl)phenyl]-3-methyl-4-(4-pyrindinyl)benzamide; GTI, 5-hydroxytryptamine-5-O-carboxymethylglycyltyrosinamide; L694247, 2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-oxadiazol-5-yl]-1H-indol-3yl] ethanamine; LY334370, 5-(4-flurobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole fumarate; LY344864,N-[(6R)-6-dimethylamino-6,7,8,9-tetrahydro-5H-carbazo-3-yl]-4-fluorobenzamide; MDL100907, (+ /–)2,3-dimethoxyphenyl-1-[2-(4-piperidine)-methanol]; NAD299, (R)-3-N,N-dicyclobutylamino-8-fluoro-[6-3H]-3,4-dihydro-2H-1-benzo pyran-5-carboxamide; NAS181, (R)-(+)-2-[[[3-(morpholinomethyl)-2H-chromen-8-yl]oxy]methyl] morpholine methane sulfonate; p-[18F]MPPF, 4-(2′-methoxyphenyl)-1-[2′-(N-2″-pyridinyl)-p-fluorobenzamido]-ethyl piperazine; PNU109291, (S)-3,4-dihydro-1-[2-[4-(4-methoxyphenyl)-1-piper-azinyl]ethyl]-N-methyl-1H-2-benzopyran-6-carboximide; RP62203, 2-[3-(4-(4-fluorophenyl)-piperazinyl)propyl]naphto[1,8- ca]isothiazole-1,1-dioxide; Ro600175, (S)-2-(6-chloro-5-fluroindol-1-yl)-1-methyethylamine; Ro630563, 4-amino-N-[2,6-bis(methylamino)pyridin-4-yl]benzene-sulphonamide; RS57639, 4-amino-5-chloro-2-methoxy benzoic acid 1-(3-[2,3-dihydrobenzo[1,4]dioxin-6yl)-propyl]-piperidin-4yl methyl ester; RS67506, 1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-(2-methyl sulphonylamino)ethyl-4-piperidinyl]-1-propanone hydrochloride; RS100235, 1-(8-amino-7-chloro-1,4-benzodioxan-5-yl)-5-((3-(3,4-dimethoxyphenyl)prop-1-yl)piperidin-4-yl)propan-1-one; RS102221, 8-[5-(5-amino 2,4-di-methoxyphenyl) 5-oxopentyl]-1,3,8-triazaspiro[4,5]decane-2,4-dione; RS127445, (2-amino-4-(4-fluoronaphthyl-1-yl)-6-isopropylpyrimidine); SB204070, 1-butyl-4-piperidinylmethyl-8-amino-7-chloro-1-4-benzoioxan-5-carboxylate; SB207710, 1-butyl-4-piperidinylmethyl-8-amino-7-iodo-1,4-benzodioxan-5-carboxylate; SB224289, 1′-methyl-5[[2′-methyl-4′-)5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl-2,3,6,7-tetra-hydrospiro[furo[2,3-f]indole-3,4′-piperidine]oxalate; SB236057, 1′-ethyl-5-(2′-methyl-4′-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indol3-3,4′-piperidine; SB242084, 6-chloro-5-methyl-1-[2-(2-methylpyridyl-3-oxy)-pyrid-5-yl carbamoyl] indoline; SB258585, 4-iodo-N-[4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-benzenesulphonamide; SB258719, (R)-3,N-dimethyl-N-[1-methyl-3-(4-methylpiperidin-1-yl)propyl]benzene sulphonamide; SB269970, (R)-3-(2-(2-(4-methylpiperidin-1-yl)ethyl)pyrrolidine-1-sulphonyl)phenol; SB271046, 5-chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulphonamide; SB357134,N-(2,5-dibro-mo-3-flurophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulphonamide; SB656104, 6-((R)-2-[2-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-ethyl]-pyrrolidine-1-sulphonyl)-1H-indole hydrochloride; SB699551, 3-cyclopentyl-N-[2-(dimethylamino)ethyl]-N-[(4′-{[(2-phenylethyl)amino]-methyl}-4-biphenylyl)methyl]propanamide dihydrochloride; SB714786, 2-methyl-5-({2-[4-(8-quinolinylmethyl)-1-piperazinyl]ethyl}oxy)qui-noline; UH301, 5-fluoro-8-hydroxy-2-(dipropylamino) tetralin; U92016A, (+)-(R)-2-cyano-N,N-dipropyl-8-amino-6,7,8,9-tetrahydro-3H-benz[e]indole; WAY100635,N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl)-cyclohexanecarboxamide trichloride; WAY163909, (7bR, 10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole

Further Reading

Barnes NM, Sharp T (1999). A review of central 5-HT receptors and their function. Neuropharmacology38: 1083–1152.

Bockaert J, Claeysen S, Becamel C, Dumuis A, Marin P (2006). Neuronal 5-HT metabotropic receptors: fine-tuning of their structure, signaling, and roles in synaptic modulation. Cell Tissue Res326: 553–572.

Bockaert J, Claeysen S, Compan V, Dumuis A (2004). 5-HT4 receptors. Curr Drug Targets CNS Neurol Disord3: 39–51.

Bojarski AJ (2006). Pharmacophore models for metabotropic 5-HT receptor ligands. Curr Top Med Chem6: 2005–2026.

Bonasera SJ, Tecott LH (2000). Mouse models of serotonin receptor function: toward a genetic dissection of serotonin systems. Pharmacol Ther88: 133–142.

Caliendo G, Santagada V, Perissutti E, Fiorino F (2005). Derivatives as 5HT1A receptor ligands - past and present. Curr Med Chem12: 1721–1753.

Gershon MD (1999). Review article: roles played by 5-hydroxytryptamine in the physiology of the bowel. Aliment Pharmacol Ther13 (Suppl 2): 15–30.

Glennon RA (2003). Higher-end serotonin receptors: 5-HT5, 5-HT6, and 5-HT7. J Med Chem46: 2795–2812.

Hartig PR, Hoyer D, Humphrey PP, Martin GR (1996). Alignment of receptor nomenclature with the human genome: classification of 5-HT1B and 5-HT1D receptor subtypes. Trends Pharmacol Sci17: 103–105.

Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ et al. (1994). International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (serotonin). Pharmacol Rev46: 157–203.

Hoyer D, Hannon JP, Martin GR (2002). Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav71: 533–554.

Hoyer D, Martin G (1997). 5-HT receptor classification and nomenclature: towards a harmonization with the human genome. Neuropharmacology36: 419–428.

Kitson SL (2007). 5-hydroxytryptamine (5-HT) receptor ligands. Curr Pharm Des13: 2621–2637.

Lanfumey L, Hamon M (2004). 5-HT1 receptors. Curr Drug Targets CNS Neurol Disord3: 1–10.

Leysen JE (2004). 5-HT2 receptors. Curr Drug Targets CNS Neurol Disord3: 11–26.

Nelson DL (2004). 5-HT5 receptors. Curr Drug Targets CNS Neurol Disord3: 53–58.

Pauwels PJ (2000). Diverse signalling by 5-hydroxytryptamine (5-HT) receptors. Biochem Pharmacol60: 1743–1750.

Sanders-Bush E, Fentress H, Hazelwood L (2003). Serotonin 5-HT2 receptors: molecular and genomic diversity. Mol Interv3: 319–330.

Thomas DR (2006). 5-ht5A receptors as a therapeutic target. Pharmacol Ther111: 707–714.

Thomas DR, Hagan JJ (2004). 5-HT7 receptors. Curr Drug Targets CNS Neurol Disord3: 81–90.

Woolley ML, Marsden CA, Fone KC (2004). 5-ht6 receptors. Curr Drug Targets CNS Neurol Disord3: 59–79.

References

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Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Acetylcholine (muscarinic)

Overview: Muscarinic acetylcholine receptors (nomenclature as agreed by NC-IUPHAR sub-committee on Muscarinic Acetylcholine Receptors, Caulfield and Birdsall, 1998) are 7TM receptors of the rhodopsin-like family where the endogenous agonist is acetylcholine. In addition to the agents listed in the table, AC-42 and desmethylclozapine have been described as selective agonists of the M1 receptor subtype via binding to a site distinct to that recognised by non-selective agonists (Spalding et al., 2002; Sur et al., 2003). There are two allosteric sites on muscarinic receptors, one defined by it binding gallamine, strychnine and brucine and the other binds KT5720, WIN62,577, WIN51,708 and staurosporine (Lazareno et al., 2000, 2002). There are selective enhancers of acetylcholine binding and action; brucine and KT5720 at M1 receptors, PG135 at M2 receptors, N-chloromethylbrucine and WIN62,577 at M3 receptors and thiochrome at M4 receptors (Birdsall and Lazareno, 2005). The allosteric site for gallamine and strychnine on M2 receptors can be labelled by [3H]dimethyl-W84 (Tränkle et al., 2003). THRX-160209 is a multivalent ligand that may achieve its selectivity for M2 receptors by binding both to the orthosteric and a nearby allosteric site (Steinfeld et al., 2007).

NomenclatureM1M2M3
Ensembl IDENSG00000168539ENSG00000181072ENSG00000133019
Principal transductionGq/11Gi/oGq/11
AntagonistsMT7 (11.0), 4-DAMP (9.2), tripitramine (8.8), darifenacin (8.3), pirenzepine (6.3-8.3), guanylpirenzepine (7.7), AFDX384 (7.3-7.5), MT3 (7.1), himbacine (6.7-7.1), AFDX116 (6.2)tripitramine (9.6), AFDX384 (8.0-9.0), 4-DAMP (8.4), himbacine (7.9-8.4), darifenacin (7.3-7.6), AFDX116 (6.7-7.3), pirenzepine (4.9-6.4), MT7 (<6), MT3 (<6), guanylpirenzepine (5.6)4-DAMP (9.3), darifenacin (9.1), AFDX384 (7.2-7.8), tripitramine (7.1-7.4), himbacine (6.9-7.2), pirenzepine (5.6-6.7), guanylpirenzepine (6.5), AFDX116 (6.1), MT3 (<6), MT7 (<6)
Probes (KD)[3H]NMS (80-150 pM), [3H]QNB (15-60 pM), [3H]pirenzepine (3-15 nM), (R,R)-quinuclidinyl-4-[18F]-fluoromethyl-benzilate (PET ligand), [11C]xanomeline (PET ligand), [11C]butylthio-TZTP (PET ligand)[3H]NMS (200-400 pM), [3H]QNB (20-50 pM), [18F]FP-TZTP (PET ligand),[3H]NMS (150-250 pM), [3H]QNB (30-90 pM), [3H]darifenacin (300 pM)
NomenclatureM4M5
Ensembl IDENSG00000180720ENSG00000184984
Principal transductionGi/oGq/11
Antagonists4-DAMP (8.9), MT3 (8.7), AFDX384 (8.0-8.7), AFDX116 (7-8.7), himbacine (7.9-8.2), tripitramine (7.8-8.2), darifenacin (8.1), pirenzepine (5.9-7.6), guanylpirenzepine (6.5), MT7 (<6)4-DAMP (9.0), darifenacin (8.6), tripitramine (7.3-7.5), guanylpirenzepine (6.8), pirenzepine (6.2-6.9), himbacine (5.4-6.5), AFDX384 (6.3), AFDX116 (5.3-5.6), MT3 (<6), MT7 (<6)
Probes (KD)[3H]NMS (50-100 pM), [3H]QNB (20-80 pM)[3H]NMS (500-700 pM), [3H]QNB (20-60 pM)

Antagonist data tabulated are pKi values determined for human recombinant receptors. MT3 (m4-toxin) and MT7 (m1-toxin1) are toxins contained with the venom of the Eastern green mamba (Dendroaspis augusticeps) (see Bradley, 2000; Potter et al., 2004).

Abbreviations: 4-DAMP, 4-diphenylacetoxy-N-methylpiperidine methiodide; AC-42, 4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piper-idine hydrogen chloride; AFDX116, (otenzepad), 1-[2-[2-(diethylaminomethyl)piperidin-1-yl]acetyl]-5H-pyrido[2,3-b][1,4]benozodiazepin-6-one; AFDX384, (±)-5,11-dihydro-11-([(2-[2-[dipropylamino)methyl]-1-piperidinyl)ethyl)amino)carbonyl)-6H-pyrido[2,3-b](1,4)benzodiaze-pine-6-one; Butylthio-TZTP, butylthio-thiadiazolyltetrahydro-1-methyl-pyridine; Dimethyl-W84, N,N'-bis[3-(1,3-dihydro-1,3-dioxo-4-methyl-2H-isoindol-2-yl)propyl]-N,N,N',N'-tetramethyl-1,6-hexanediaminium diiodide; FP-TZTP, [3-(3-(3-Fluoropropyl)thio)-1,2,5-thiadiazol-4-yl]1,2,5,6-tetrahydro-1-methylpyridine; KT5720, (9S,10S,12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid hexyl ester; NMS, N-methylscopolamine; PG135, (3aS,12R,12aS,12bR)-2-amino-2,3,3a,4,11,12a,12b-octahydro-10-hydroxyisoquino[2,1,8-lma]carbazol-5(1H)-one hydrochloride; QNB, 3-quinuclidinylbenzilate; THRX160209, 4-{N-[7-(3-(S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hept-1-yl]-N-(n-propyl)amino}-1-(2,6-dimethoxy-benzyl)piperidine;WIN51,708, 17-β-hydroxy-17-α-ethynyl-5-α-androstano[3,2-b]pyrimido[1,2-a]benzimidazole; WIN62,577, 17-β-hydroxy-17-α-ethynyl-Δ4-androstano[3,2-b]pyrimido[1,2-a]benzimidazole

Further Reading

Abrams P, Andersson KE, Buccafusco JI, Chapple C, De Groat WC, Fryer AD et al. (2006). Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder. Br J Pharmacol148: 565–578.

Birdsall NJM, Lazareno S (2005). Allosterism at muscarinic receptors: ligands and mechanisms. Mini Rev Med Chem5: 523–543.

Bradley KN (2000). Muscarinic toxins from the green mamba. Pharmacol Ther85: 87–109.

Caulfield MP, Birdsall NJM (1998). International Union of Pharmacology. XVII Classification of muscarinic acetylcholine receptors. Pharmacol Rev50: 279–290.

Eckelman WC (2006). Imaging of muscarinic receptors in the central nervous system. Curr Pharm Des12: 3901–3913.

Eglen RM (2005). Muscarinic receptor subtype pharmacology and physiology. Prog Med Chem43: 105–136.

Eglen RM (2006). Muscarinic receptor subtypes in neuronal and non-neuronal cholinergic function. Auton Autocoid Pharmacol26: 219–233.

Holzgrabe U, De Amici M, Mohr K (2006). Allosteric modulators and selective agonists of muscarinic receptors. J Mol Neurosci30: 165–168.

Ishii M, Kurachi Y (2006). Muscarinic acetylcholine receptors. Curr Pharm Des12: 3573–3581.

Potter LT, Flynn DD, Liang JS, McCollum MH (2004). Studies of muscarinic neurotransmission with antimuscarinic toxins. Prog Brain Res145: 121–128.

Wess J, Eglen RM, Gautam D (2007). Muscarinic acetylcholine receptors: mutant mice provide new insights for drug development. Nat Rev Drug Discov6: 721–733.

References

Lazareno S et al. (2002). Mol Pharmacol62: 1492–1505.

Lazareno S et al. (2000). Mol Pharmacol58: 194–207.

Spalding TA et al. (2002). Mol Pharmacol61: 1297–1302.

Steinfeld T et al. (2007). Mol Pharmacol72: 291–302.

Sur C et al. (2003). Proc Natl Acad Sci USA100: 13674–13679.

Tränkle C et al. (2003). Mol Pharmacol64: 180–190.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Adenosine

Overview: Adenosine receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Adenosine Receptors; Fredholm et al., 2001) are activated by the endogenous ligand adenosine (potentially inosine also at A3 receptors). NECA is a non-selective agonist, while XAC and CGS15943 display submicromolar affinity at all four adenosine receptors (Klotz et al., 1998; Ongini et al., 1999).

NomenclatureA1A2AA2BA3
Ensembl IDENSG00000163485ENSG00000128271ENSG00000170425ENSG00000121933
Principal transductionGi/oGsGsGi/o
Selective agonistsCPA, CCPA, S-ENBA, GR79236CGS21680, HENECA, ATL-146e (Peirce et al., 2001)Bay60-6583 (Eckle et al., 2007)2-Cl-IB-MECA, IB-MECA
Selective antagonistsDPCPX (8.5)ZM241385 (9.0), SCH58261 (7.9-9.5)MRS1754 (8.7), MRS1706 (8.4), PSB1115 (7.7)MRS1220 (8.8), VUF5574 (8.4, van Muijlwijk-Koezen et al., 2000), MRS1523 (7.7), MRS1191 (7.0)
Probes[3H]-CCPA, [3H]-DPCPX (0.6-1.2 nM)[3H]-CGS21680, [3H]-ZM241385 (0.8 nM)[3H]-MRS1754 (1.1 nM)[125I]-AB-MECA (0.6 nM)

Adenosine inhibits many intracellular ATP-utilising enzymes, including adenylyl cyclase (P-site). A pseudogene exists for the A2B adenosine receptor (ENSG00000182537) with 79% identity to the A2B adenosine receptor cDNA coding sequence, but which is unable to encode a functional receptor (Jacobson et al., 1995). DPCPX also exhibits antagonism at A2B receptors (pKi ca. 7, Alexander et al., 1996; Klotz et al., 1998). HENECA also shows activity at A3 receptors (Varani et al., 1998). Antagonists at A3 receptors exhibit marked species differences, such that only MRS1523 and MRS1191 are selective at the rat A3 receptor. In the absence of other adenosine receptors, [3H]-DPCPX and [3H]-ZM241385 can also be used to label A2B receptors (KD ca. 30 and 60 nM, respectively). [125I]-AB-MECA also binds to A1 receptors (Klotz et al., 1998). [3H]-CGS21680 is relatively selective for A2A receptors, but may also bind to other sites in cerebral cortex (Johansson & Fredholm, 1995; Cunha et al., 1996). [3H]-NECA binds to other non-receptor elements, which also recognise adenosine (e.g. Lorenzen et al., 1996). XAC-BY630 has been described as a fluorescent antagonist for labelling A1 adenosine receptors in living cells, although activity at other adenosine receptors was not examined (Briddon et al., 2004).

Adenosine has also been reported to act as a partial agonist at the ghrelin receptor (Smith et al., 2000), but this has been questioned (Johansson et al., 2005).

Abbreviations: AB-MECA,N6-(4-aminobenzyl)-adenosine-5′-N-methyluronamide; ATL-146e, 4-{3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihy-droxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid methyl ester; Bay 60-6583, 2-(6-amino-3,5-dicyano-4-(4-(cyclopropylmethoxy)phenyl) pyridin-2-ylthio)acetamide; CCPA, 2-chloro-N6-cyclopentyladenosine; CGS15943, 5-amino-9-chloro-2-(2-furyl)1,2,4-triazolo[1,5-c]quinazoline; CGS21680, 2-(4-[2-carboxyethyl]-phenethylamino)adenosine-5′-N-ethyluronamide; 2Cl-IB-MECA, 2-chloro-N6-(3-iodobenzyl)adenosine-5′-N-methyluronamide; CPA,N6-cyclopentyladenosine; DPCPX, 8-cyclopentyl-1,3-dipropylxanthine; GR79236, N-[(1s,2s)-2-hydroxycyclopentyl adenosine; HENECA, 2-(1-(E)-hexenyl)adenosine-5′-N-ethyluronamide; MRS1191, 1,4-dihydro-2-methyl-6-phenyl-4-(phenylethynyl)-3,5-pyridinedicarboxylic acid,3-ethyl 5-(phenylmethyl) ester; MRS1220, 9-chloro-2-(2-furyl)5-phenylace-tylamino[1,2,4]triazolo[1,5c]quinazoline; MRS1523, 2,3-ethyl-4,5-dipropyl-6-phenylpyridine-3-thiocarboxylate-5-carboxylate; MRS1706,N-(4-acetylphenyl)-2-(4-[2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl]phenoxy)acetamide; MRS1754, 8-(4-[{(4-cyanophenyl)carbamoyl methyl}oxy]phenyl)-1,3-di(n-propyl)xanthine; NECA, adenosine-5′-N-ethyluronamide; PSB1115, 4-[2,3,6,7-tetrahydro-2,6-dioxo-1-propyl-1H-purin-8-yl)benzenesulphonicacid; S-ENBA, (2S)-N6-(2-endonorbanyl)adenosine; SCH58261, 5-amino-2-(2-furyl)-7-phenylethyl-pyrazolo[4,3-e]-1,2,4-triazolo[1,5c] pyrimidine; VUF5574,N-(2-methoxyphenyl)-N-(2-[3-pyridyl]quinazolin-4-yl)urea; XAC, 8-(4-[{([{2-aminoethyl}amino]carbo-nyl)methyl}oxy]phenyl)-1,3-dipropylxanthine,also known as xanthine amine congener; XAC-BY630,N-(2-aminoethyl)-2-[4-(2,6-dioxo-1,3-dipropyl-7H-purin-8-yl)phenoxy]acetamide; ZM241385, 4-(2-[7-amino-2-{2-furyl}{1,2,4}triazolo{2,3-a}{1,3,5}triazin-5-yl amino]ethyl)phenol

Further Reading

Fredholm BB, IJzerman AP, Jacobson KA, Klotz KN, Linden J (2001). International union of pharmacology. XXV. nomenclature and classification of adenosine receptors. Pharmacol Rev53: 527–552.

Fredholm BB, Chen JF, Masino SA, Vaugeois JM (2005). Actions of adenosine at its receptors in the CNS: insights from knockouts and drugs. Annu Rev Pharmacol Toxicol45: 385–412.

Jacobson KA, Gao ZG (2006). Adenosine receptors as therapeutic targets. Nat Rev Drug Discovery5: 247–264.

Klinger M, Freissmuth M, Nanoff C (2002). Adenosine receptors: G protein-mediated signalling and the role of accessory proteins. Cell Signal14: 99–108.

Latini S, Pedata F (2001). Adenosine in the central nervous system: release mechanisms and extracellular concentrations. J Neurochem79: 463–484.

Yaar R, Jones MR, Chen JF, Ravid K (2005). Animal models for the study of adenosine receptor function. J Cell Physiol202: 9–20.

References

Alexander SPH et al. (1996). Br J Pharmacol119: 1286–1290.

Briddon SJ et al. (2004). Proc Natl Acad Sci U S A101: 4673–4678.

Cunha RA et al. (1996). Naunyn-Schmiedeberg's Arch Pharmacol353: 261–271.

Eckle T et al. (2007). Circulation115: 1581–1590.

Johansson B, Fredholm BB (1995). Neuropharmacology34: 393–403.

Johansson S et al. (2005). Biochem Pharmacol70: 598–605.

Klotz K-N et al. (1998). Naunyn-Schmiedeberg's Arch Pharmacol357: 1–9.

Lorenzen A et al. (1996). Biochem Pharmacol52: 1375–1385.

Ongini E et al. (1999). Naunyn-Schmiedeberg's Arch Pharmacol359: 7–10.

Peirce SM et al. (2001). Am J Physiol -Heart Circ Physiol281: H67–H74.

Smith RG et al. (2000). Biochem Biophys Res Commun276: 1306–1313.

van Muijlwijk-Koezen JE et al. (2000). J Med Chem43: 2227–2238.

Varani K et al. (1998). Life Sci63: PL81–PL87.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Adiponectin

Overview: Adiponectin receptors (provisional nomenclature, ENSF00000002482) respond to the 30kDa complement-related protein hormone adiponectin (also known as adipocyte, C1q and collagen domain-containing protein; ACRP30, adipose most abundant gene transcript 1; apM-1; gelatin-binding protein; ENSG00000181092) originally cloned from adipocytes (Maeda et al., 1996). Although sequence data suggest 7TM domains, immunological evidence indicates that, contrary to typical 7TM topology, the carboxyl terminus is extracellular, while the amino terminus is intracellular (Yamauchi et al., 2003). Signalling through these receptors appears to avoid G-proteins and rather activates protein phosphorylation via AMP-activated protein kinase and MAP kinase pathways (Yamauchi et al., 2003).

NomenclatureAdipo1Adipo2
Other namesAdipoR1, progestin and adipoQ receptor family member I, CG145AdipoR2, progestin and adipoQ receptor family member II
Ensembl IDENSG00000159346ENSG00000006831
Rank order of potencygAdipo>flAdipogAdipo = flAdipo

T-Cadherin has also been suggested to be a receptor for (hexameric) adiponectin (Hug et al., 2004).

Abbreviations: flAdipo, full-length adiponectin; gAdipo, globular adiponectin

Further Reading

Gil-Campos M, Canete RR, Gil A (2004). Adiponectin, the missing link in insulin resistance and obesity. Clin Nutr23: 963–974.

Goldstein BJ, Scalia R (2004). Adiponectin: A novel adipokine linking adipocytes and vascular function. J Clin Endocrinol Metab89: 2563–2568.

Haluzik M, Parizkova J, Haluzik MM (2004). Adiponectin and its role in the obesity-induced insulin resistance and related complications. Physiol Res53: 123–129.

Hopkins TA, Ouchi N, Shibata R, Walsh K (2007). Adiponectin actions in the cardiovascular system. Cardiovasc Res74: 11–18.

Hug C, Lodish HF (2005). The role of the adipocyte hormone adiponectin in cardiovascular disease. Curr Opin Pharmacol5: 129–134.

Kadowaki T, Yamauchi T (2005). Adiponectin and adiponectin receptors. Endocr Rev26: 439–451.

Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K (2006). Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest116: 1784–1792.

Kelesidis I, Kelesidis T, Mantzoros CS (2006). Adiponectin and cancer: a systematic review. Br J Cancer94: 1221–1225.

Lafontan M (2005). Fat cells: afferent and efferent messages define new approaches to treat obesity. Annu Rev Pharmacol Toxicol45: 119–146.

Okamoto Y, Kihara S, Funahashi T, Matsuzawa Y, Libby P (2006). Adiponectin: a key adipocytokine in metabolic syndrome. Clin Sci 110: 267–278.

Ouchi N, Shibata R, Walsh K (2006). Cardioprotection by adiponectin. Trends Cardiovasc Med16: 141–146.

Szmitko PE, Teoh H, Stewart DJ, Verma S (2007). Adiponectin and cardiovascular disease: state of the art? Am J Physiol -Heart Circ Physiol292: H1655–H1663.

Vasseur F (2006). Adiponectin and its receptors: partners contributing to the ‘vicious circle’ leading to the metabolic syndrome? Pharmacol Res53: 478–481.

References

Hug C et al. (2004). Proc Natl Acad Sci USA101: 10308–10313.

Maeda K et al. (1996). Biochem Biophys Res Commun221: 286–289.

Yamauchi T et al. (2003). Nature423: 762–769.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Adrenoceptors, α1

Overview: α1-Adrenoceptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Adrenoceptors, Bylund et al., 1994) are 7TM receptors activated by the endogenous agonists adrenaline and noradrenaline with equal potency. Phenylephrine, methoxamine and cirazoline are agonists selective for α1-adrenoceptors relative to α2-adrenoceptors, while prazosin (8.5-10.5) and corynanthine (6.5-7.5) are considered selective for α1-adrenoceptors relative to α2-adrenoceptors. [3H]-Prazosin (0.25 nM) and [125I]-HEAT (0.1 nM; also known as BE2254) are relatively selective radioligands. Numerous splice variants of the α1-adrenoceptors exist, some of which may display a different spectrum of signalling properties. One polymorphism of the α1A-adrenoceptor has been described but is not associated with disease.

Nomenclatureα1Aα1Bα1D
Other namesα1a, α1cα1bα1A/D, α1a/d
Ensembl IDENSG00000120907ENSG00000170214ENSG00000171873
Principal transductionGq/11Gq/11Gq/11
Selective agonistsA61603, dabuzalgron (Blue et al., 2004)
Selective antagonistsTamsulosin (10.5), KMD3213 (10.4), (+)niguldipine (10.0), SNAP5089 (9.7)BMY7378 (8.4)

The clone originally called the α1C-adrenoceptor corresponds to the pharmacologically defined α1A-adrenoceptor (see Ford et al., 1994; Hieble et al., 1995). Some tissues possess α1-adrenoceptors that display relatively low affinity in functional and binding assays for prazosin (pKi <9) that might represent different receptor states (termed α1L-adrenoceptors, Ford et al., 1997; Morishima et al., 2007). α1A-Adrenoceptor C-terminal splice variants form homo and heterodimers, but fail to generate a functional α1L adrenoceptor (Ramsay et al., 2004). α1D-Adrenoceptors form heterodimers with α1B- or β2-adrenoceptors that show increased cell-surface expression (Uberti et al., 2005). Heterodimers formed between α1D-and α1B-adrenoceptors have distinct functional properties (Hague et al., 2004). (+)Niguldipine also has high affinity for L-type Ca2+ channels.

Abbreviations: A61603, N-(5-[4,5-dihydro-1H-imidazol-2-y]-2-hydroxy-5,6,7,8-tetrahydronaphthalen1-yl)methanesulfonamide hydrobromide; BMY7378, 8-(2-[4-{2methoxyphenyl}-1-piperazinyl]ethyl)-8-azaspiro[4,5]decane-7,9-dione dihydrochloride; HEAT, 2-β-4-hydroxy-3-iodophenylethylaminomethyltetralone; ICI118551, (-)-1-(2,3-[dihydro-7-methyl-1H-inden-4-yl]oxy)-3-([1-methylethyl]-amino)-2-butanol; KMD3213, (-)-(R)-1-(3-hydroxypropyl)-5-(2-[2-{2-(2,2,2-trifluoroethoxy)phenoxyl}ethylamino]propyl)indoline-7-carboxamide, also known as silodosin; RS17053, N-[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro-α,α-dimethyl-1H-indole-3-ethanamide; SNAP5089, 2,6-di-methyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate-N-[3-(4,4-diphenylpiperidin-1-yl)propyl]amide methyl ester; SNAP5272, car-boxamide-2,6-diethyl-1,4-dihydro-3-[N-(3-[4-hydroxy-4-phenylpiperidinyl]propyl)]carboxamido-4-(4-nitrophenyl)

Further Reading

Bylund DB, Eikenberg DC, Hieble JP, Langer SZ, Lefkowitz RJ, Minneman KP et al. (1994). International Union of Pharmacology IV. Nomenclature of adrenoceptors. Pharmacol Rev46: 121–136.

Cotecchia S (2007). Constitutive activity and inverse agonism at the α1 adrenoceptors. Biochem Pharmacol73: 1076–1083.

Ford APDW, Williams TJ, Blue DR, Clarke DE (1994). α1-Adrenoceptor classification: sharpening Occam's razor. Trends Pharmacol Sci15: 167–170.

Hein L (2006). Adrenoceptors and signal transduction in neurons. Cell Tissue Res326: 541–551.

Hieble JP, Bylund DB, Clarke DE, Eikenburg DC, Langer SZ, Lefkowitz RJ et al. (1995). International Union of Pharmacology. X. Recommendation for nomenclature of α1-adrenoceptors: consensus update. Pharmacol Rev47: 267–270.

Koshimizu TA, Tanoue A, Tsujimoto G (2007). Clinical implications from studies of α1 adrenergic receptor knockout mice. Biochem Pharmacol73: 1107-1112.

Tanoue A, Koshimizu TA, Shibata K, Nasa Y, Takeo S, Tsujimoto G (2003). Insights into α1 adrenoceptor function in health and disease from transgenic animal studies. Trends Endocrinol Metab14: 107–113.

References

Blue DR et al. (2004). BJU Int93: 162–170.

Ford APDW et al. (1997). Br J Pharmacol121: 1127–1135.

Hague C et al. (2004). J Pharmacol Exp Ther309: 388–397.

Morishima S et al. (2007). J Urol177: 377–381.

Ramsay D et al. (2004). Mol Pharmacol66: 228–239.

Uberti MA et al. (2005). J Pharmacol Exp Ther313: 16–23.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1-S209.

Adrenoceptors, α2

Overview: α2-Adrenoceptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Adrenoceptors; Bylund et al., 1994) are 7TM receptors, activated by endogenous agonists with a relative potency of adrenaline> noradrenaline. UK14304 and BHT920 are agonists selective for α2-adrenoceptors relative to α1-adrenoceptors. Rauwolscine (9.0) and yohimbine (9.0) are antagonists selective for α2-adrenoceptors relative to α1-adrenoceptors. [3H]-rauwolscine (1 nM), [3H]-UK14304 (5 nM) and [3H]-RX821002 (0.5 and 0.1 nM at α2C) are relatively selective radioligands. There is species variation in the pharmacology of the α2A-adrenoceptor; for example, yohimbine, rauwolscine and oxymetazoline have an ∼20-fold lower affinity for rat, mouse and bovine α2A-adrenoceptors compared to the human receptor. These α2A orthologues are sometimes referred to as α2D-adrenoceptors. Multiple mutations of α2-adrenoceptors have been described, some of which are associated with alterations in function.

Nomenclatureα2Aα2Bα2C
Other namesα2D
Ensembl IDENSG00000150594ENSG00000181210ENSG00000184160
Principal transductionGi/oGii/oGi/o
Selective agonistsOxymetazoline
Selective antagonistsBRL44408 (8.0)ARC239 (8.0), prazosin (7.5), imiloxan (7.3)ARC239 (8.0), prazosin (7.5)

Oxymetazoline is a partial agonist. Binding sites for imidazolines, distinct from α2-adrenoceptors, have been identified and classified as I1, I2 and I3 sites, but with a function other than coupling to G-proteins; catecholamines have a low affinity for these sites.

Abbreviations: ARC239, 2-(2,4-[O-methoxyphenyl]-piperazin)-1-yl; BHT920, 6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]-azepine; BRL44408, 2-(2H-[1-methyl-1,3-dihydroisoindole]methyl)-4,5-dihydroimidazole; MK912, (2S,12bS)1′,3′-dimethylspiro(1,3,4,5′,6,6′,7,12b-oc-tahydro-2H-benzo[b]furo[2,3-a]quinolizine)-2,4′-pyrimidin-2′-one; RX821002, 2-(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline; UK14304, 5-bromo-6-[2-imidazolin-2-ylamino]quinoxaline, also known as brimonidine

Further Reading

Buscher R, Herrmann V, Insel PA (1999). Human adrenoceptor polymorphisms: evolving recognition of clinical importance. Trends Pharmacol Sci20: 94–99.

Bylund DB, Eikenberg DC, Hieble JP, Langer SZ, Lefkowitz RJ, Minneman KP et al. (1994). International Union of Pharmacology IV. Nomenclature of adrenoceptors. Pharmacol Rev46: 121–136.

Docherty JR (1998). Subtypes of functional α1- and α2-adrenoceptors. Eur J Pharmacol361: 1–15.

Guimaraes S, Moura D (2001). Vascular adrenoceptors: an update. Pharmacol Rev53: 319–356.

Hein L (2006). Adrenoceptors and signal transduction in neurons. Cell Tissue Res326: 541–551.

Kable JW, Murrin LC, Bylund DB (2000). In vivo gene modification elucidates subtype-specific functions of α2-adrenergic receptors. J Pharmacol Exp Ther293: 1–7.

Koch WJ, Lefkowitz RJ, Rockman HA (2000). Functional consequences of altering myocardial adrenergic receptor signaling. Annu Rev Physiol62: 237–260.

Philipp M, Brede M, Hein L (2002). Physiological significance of α2-adrenergic receptor subtype diversity: one receptor is not enough. Am J Physiol -Regul Integr Comp Physiol283: R287–R295.

Philipp M, Hein L (2004). Adrenergic receptor knockout mice: distinct functions of 9 receptor subtypes. Pharmacol Ther101: 65–74.

Rohrer DK, Kobilka BK (1998). G protein-coupled receptors: functional and mechanistic insights through altered gene expression. Physiol Rev78: 35–52.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Adrenoceptors, β

Overview: β-Adrenoceptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Adrenoceptors, Bylund et al., 1994) are 7TM receptors, activated by the endogenous agonists adrenaline and noradrenaline. Isoprenaline is a synthetic agonist selective for β-adrenoceptors relative to α1- and α2-adrenoceptors, while propranolol (pKi 8.2-9.2) and cyanopindolol (pKi 10.0-11.0) are relatively selective antagonists. β3-Adrenoceptors are relatively resistant to blockade by propranolol (pKi 5.8-7.0), but can be blocked with high concentrations of cyanopindolol (pKi 9.0). Numerous polymorphisms exist for the β1- and β2-adrenoceptors and some of these are associated with alterations in signalling in response to agonists. These polymorphisms are likely to be associated with altered responses to drugs.

Nomenclatureβ1β2β3
Other namesatypical β
Ensembl IDENSG00000043591ENSG00000169252ENSG00000147477
Principal transductionGsGsGs
Rank order of potencyNoradenaline > adrenalineAdrenaline > noradenalineNoradenaline = adrenaline
Selective agonistsNoradrenaline, xamoterol, RO363, denopamineProcaterol, zinterol, salmeterol, formoterol, terbutaline, fenoterolBRL37344, CL316243, CGP12177A, carazolol, L742791, SB251023
Selective antagonists ProbesCGP20712A (8.5-9.3), betaxolol (8.5), atenolol (7.6) [125I]-ICYP (20-50 pM) + 70 nM ICI118551ICI118551 (8.3-9.2) [125I]-ICYP (20-50 pM) + 100 nM CGP20712ASR59230A (8.8), L748328 (8.5) [125I]-ICYP (0.5 nM)

Noradrenaline, xamoterol and RO363 show selectivity for β1- relative to β2-adrenoceptors. All β-adrenoceptors couple to Gs (activating adenylyl cyclase and elevating cyclic AMP levels), but it is also clear that they activate many other signalling pathways, particularly mitogen-activated protein kinases. Many antagonists at β1- and β2-adrenoceptors are agonists at β3-adrenoceptors (CL316243, CGP12177A and carazolol). Many ‘antagonists’ appear to be able to activate selectively mitogen-activate protein kinase pathways (Baker et al., 2003a; Galandrin and Bouvier, 2006; Sato et al., 2007). SR59230A has reasonably high affinity at β3-adrenoceptors (Manara et al., 1996), but does not discriminate well between the three β-adrenoceptor subtypes (Candelore et al., 1999) and has been reported to have lower affinity for the β3-adrenoceptor in some circumstances (Kaumann and Molenaar, 1996).

Pharmacological differences exist between human and mouse β3-adrenoceptors, and the ‘rodent selective’ agonists BRL37344 and CL316243 have low efficacy at the human β3-adrenoceptor. The β3-adrenoceptor has introns, but splice variants have only been described for the mouse (Evans et al., 1999). The β-adrenoceptor cloned from turkey (termed the β4c, t428 SwissProt P43141) has a pharmacology that is intermediate between β2- and β3-adrenoceptors (Chen et al., 1994). The ‘putative β4-adrenoceptor’ is not a novel receptor but is likely to represent an alternative site of interaction of CGP12177A and other nonconventional partial agonists at β1-adrenoceptors, since ‘putative β4-adrenoceptor'-mediated agonist effects of CGP12177A are absent in mice lacking β1-adrenoceptors (Konkar et al., 2000; Kaumann et al., 2001).

Radioligand binding to define β1- and β2-adrenoceptors can be conducted in the presence of a ‘saturating’ concentration of the β1- or β2-adrenoceptor-selective antagonist. [3H]-CGP12177 or [3H]-dihydroalprenolol can be used in place of [125I]-ICYP. Binding of a fluorescent analogue of CGP12177 to β2-adrenoceptors in living cells has been described (Baker et al., 2003b).

Abbreviations: BRL37344, sodium 4-(2-[2-hydroxy-3-chlorophenyl}ethylamino]propyl)phenoxyacetate; CGP12177A, (-)-4-(3-tert-butylamino-2-hydroxypropoxy)-benzimidazol-2-one; CGP20712A, 2-hydroxy-5-(2-[{2-hydroxy-3-(4-[1-methyl-4-trifluoromethyl-2-imidazolyl]phenoxy)-propyl}amino]ethoxy)benzamide; CL316243 disodium(R,R)-5-(2-[{2-(3-chlorophenyl)-2-hydroxyethyl}-amino]propyl)-1,3-benzodioxole-2,2,dicarboxylate; ICYP, iodocyanopindolol; I742791, (S)-N-(4-[2-{(3-[4-hydroxyphenoxy]-2-hydroxypropyl)amino}ethyl]phenyl)-4-iodobenzene-sulfonamide; L748328, (S)-N-(4-[2-{(3-[3-{aminosulfonyl}phenoxy]-2-hydroxypropyl)-amino}ethyl]phenyl)benzenesulfonamide; RO363, (-)-1-(3,4-dimethoxyphenethylamino)-3-(3,4-dihdroxyphenoxy)-2-propanol)oxalate; SB251023, (4-[1-{2-(S)-hydroxy-3-(4-hydroxyphenoxy)-propyl-amino}cyclopentylmethyl]phenoxymethyl)phenylphosphonic acid lithium salt; SR59230A, 3-(2-ethylphenoxy)-1([1 s]-1,2,3,4-tetrahydronaphth-1-ylamino)-2S-propanol oxalate.

Further Reading

Bylund DB, Eikenberg DC, Hieble JP, Langer SZ, Lefkowitz RJ, Minneman KP et al. (1994). International Union of Pharmacology IV. Nomenclature of adrenoceptors. Pharmacol Rev46: 121–136.

Kirstein SL, Insel PA (2004). Autonomic nervous system pharmacogenomics: a progress report. Pharmacol Rev56: 31–52.

Leineweber K, Buscher R, Bruck H, Brodde OE (2004). Adrenoceptor polymorphisms. Naunyn-Schmiedeberg's Arch Pharmacol369: 1–22.

Philipp M, Hein L (2004). Adrenergic receptor knockout mice: distinct functions of 9 receptor subtypes. Pharmacol Ther101: 65–74.

References

Baker JG et al. (2003a). Mol Pharmacol64: 1357–1369.

Baker JG et al. (2003b). Br J Pharmacol139: 232–242.

Candelore MR et al. (1999). J Pharmacol Exp Ther290: 649–655.

Chen XH et al. (1994). J Biol Chem269: 24810–24819.

Evans BA et al. (1999). Br J Pharmacol127: 1525–1531.

Galandrin S, Bouvier M (2006). Mol Pharmacol70: 1575–1584.

Kaumann AJ et al. (2001). Naunyn-Schmiedeberg's Arch Pharmacol363: 87–93.

Kaumann AJ, Molenaar P (1996). Br J Pharmacol118: 2085–2098.

Konkar AA et al. (2000). Mol Pharmacol57: 252–258.

Manara L et al. (1996). Br J Pharmacol117: 435–442.

Sato M et al. (2007). Mol Pharmacol72: 1359–1368.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Anaphylatoxin and chemotactic peptide

Overview: Anaphylatoxin and chemotactic peptide receptors (provisional nomenclature) are activated by the endogenous B75 amino-acid anaphylatoxin polypeptides C3a (ENSG00000125730) and C5a (ENSG00000106804), generated upon stimulation of the complement cascade. The fMLP receptor responds to exogenous ligands such as the bacterial product formyl-Met-Leu-Phe (fMLP) and endogenous ligands such as annexin I (ENSG00000135046), cathepsin G (ENSG00000100448) and spinorphin, derived from β-haemoglobin (ENSG00000188170).

NomenclatureC3aC5afMLP
Other namesAZ3B, HNFAG09CD88Formyl peptide, FPR
Ensembl IDENSG00000171860ENSG00000134830ENSG00000171051
Principal transductionGi/o, GzGi/o, Gz, G16 (Buhl et al., 1993)Gi/o, Gz
Rank order of potencyC3a> C5a (Ames et al., 1996)C5a, C5a des Arg> C3a (Ames et al., 1996)fMLP>Cathepsin G>Annexin I (Le et al., 2002; Sun et al., 2004)
Selective agonistsTrp-Trp-Gly-Lys-Lys-Tyr-Arg-Ala-Ser-Lys-Leu-Gly-Leu-Ala-Arg (Ames et al., 1997)Phe-Lys-Pro-Cha-Cha-Phe-Lys-D-Cha-Cha-D-Arg (Konteatis et al., 1994), S19 (Yamamoto, 2000) fMLP (Le et al., 1999) 
Selective antagonistsSB290157 (pIC50 7.5, Ames et al., 2001)NMe-Phe-Lys-Pro-D-Cha-Trp-D-Arg (Konteatis et al., 1994), AcPhe-Orn-Pro-D-Cha-Trp-Arg (Wong et al., 1998), W54011 (8.7, Sumichika et al., 2002), CHIPS (Postma et al., 2004)Cyclosporin H (6.3-7.0, Wenzel-Seifert and Seifert, 1993), BOC-PLPLP (6.0-6.5, Wenzel-Seifert and Seifert, 1993), spinorphin (4, Liang et al., 2001)
Probes[125I]-C3a[125I]-C5a[3H]-fMLP

SB290157 has also been reported to have agonist properties (Mathieu et al., 2005). A putative chemoattractant receptor termed C5L2 (also known as GPR77, ENSG00000134830) binds [125I]-C5a, with no clear signalling function, but a putative role opposing inflammatory responses (Cain and Monk, 2002; Gao et al., 2005; Gavrilyuk et al., 2005). Binding to this site may be displaced with the rank order C5a des Arg>C5a (Cain and Monk, 2002; Okinaga et al., 2003), while there is controversy over the ability of C3a and C3a des Arg to compete (Kalant et al., 2003; Okinaga et al., 2003; Honczarenko et al., 2005; Kalant et al., 2005).

Abbreviations: BOC-PLPLP, Boc-Phe-Leu-Phe-Leu-Phe; CHIPS, chemotaxis inhibitory protein of Staphylococcus aureus; SB290157, N2-([2,2-diphenylethoxy]acetyl)-L-arg; W54011, N0-([4-dimethylaminophenyl]methyl)-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphtha-len-1-carboxamide hydrochloride

Further Reading

Allegretti M, Moriconi A, Beccari AR, Di Bitondo R, Bizzarri C, Bertini R et al. (2005). Targeting C5a: recent advances in drug discovery. Curr Med Chem12: 217–236.

Guo RF, Ward PA (2005). Role of C5a in inflammatory responses. Annu Rev Immunol23: 821–852.

Monk PN, Scola AM, Madala P, Fairlie DP (2007). Function, structure and therapeutic potential of complement C5a receptors. Br J Pharmacol, in press.

Panaro MA, Acquafredda A, Sisto M, Lisi S, Maffione AB, Mitolo V (2006). Biological role of the N-formyl peptide receptors. Immunopharmacol Immunotoxicol28: 103–127.

Sallusto F, Mackay CR (2004). Chemoattractants and their receptors in homeostasis and inflammation. Curr Opin Immunol16: 724–731.

Ward PA (2004). The dark side of C5a in sepsis. Nature Reviews Immunology4: 133–142.

References

Ames RS et al. (2001). J Immunol166: 6341–6348.

Buhl AM et al. (1993). FEBS Lett323: 132–134.

Cain SA, Monk PN (2002). J Biol Chem277: 7165–7169.

Gao H et al. (2005). FASEB J19: 1003–1005.

Gavrilyuk V et al. (2005). J Neurochem92: 1140–1149.

Honczarenko M et al. (2005). Leukemia19: 1682–1683.

Kalant D et al. (2003). J Biol Chem278: 11123–11129.

Kalant D et al. (2005). J Biol Chem280: 23936–23944.

Konteatis ZD et al. (1994). J Immunol153: 4200–4205.

Le Y et al. (1999). J Immunol163: 6777–6784.

Le Y et al. (2002). Trends Immunol23: 541–548.

Liang TS et al. (2001). J Immunol167: 6609–6614.

Mathieu MC et al. (2005). Immunol Lett100: 139–145.

Okinaga S et al. (2003). Biochemistry42: 9406–9415.

Postma B et al. (2004). J Immunol172: 6994–7001.

Sumichika H et al. (2002). J Biol Chem277: 49403–49407.

Sun R et al. (2004). J Immunol173: 428–436.

Wenzel-Seifert K, Seifert R (1993). J Immunol150: 4591–4599.

Wong AK et al. (1998). J Med Chem41: 3417–3425.

Yamamoto T (2000). Pathol Int50: 863–871.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Angiotensin

Overview: The actions of angiotensin II (Ang II) are mediated by AT1 and AT2 receptors (nomenclature agreed by the NC-IUPHAR Subcommittee on Angiotensin Receptors; see de Gasparo et al., 2000), which have around 30% sequence similarity. AT1 receptors are predominantly coupled to Gq/11. Most species express a single AT1 gene, but two related AT1A and AT1B receptor genes are expressed in rodents. The AT2 receptor counteracts several of the growth responses initiated by the AT1 receptors. The AT2 receptor is much less abundant than the AT1 receptor in adult tissues and is upregulated in pathological conditions. Endogenous ligands are Ang II and angiotensin III (Ang III), while angiotensin I is weakly active in some systems.

NomenclatureAT1AT2
Ensembl IDENSG00000144891ENSG00000180772
Principal transductionGq/11Tyr & Ser/Thr phosphatases
Selective agonistsL162313[p-NH2-Phe6]-Ang II, CGP42112
Selective antagonistsEXP3174, eprosartan, valsartan, irbesartan, losartanPD123319, PD123177
Probes[3H]-A81988, [3H]-L158809, [3H]-eprosartan, [3H]-losartan, [125I]-EXP985[125I]-CGP42112

There is also evidence for an AT4 receptor that specifically binds angiotensin IV and is located in the brain and kidney. An additional putative endogenous ligand for the AT4 receptor has been described (LVV-hemorphin, a globin decapeptide) (Moeller et al., 1997). The AT1 and bradykinin B2 receptors have been proposed to form a heterodimeric complex (AbdAlla et al., 2000). The antagonist activity of CGP42112 has also been reported (Lokuta et al., 1995). Novel AT1 receptor antagonists bearing substituted 4-phenylquinoline moieties have recently been designed and synthesized. The best of these compounds bind to AT1 receptors with nanomolar affinity and are slightly more potent than losartan in functional studies (Cappelli et al., 2004).

Abbreviations: A81988, 2(N-n-propyl-N-[{2′-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]amino)pyridine-3-carboxylate; CGP42112A, nicotinicacid-Tyr-(N-benzoylcarbonyl-Arg)-Lys-His-Pro-Ile-OH; eprosartan, (E)-α-([2-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]methylene)-2-thiophenepropanoate; EXP3174, n-butyl-4-chloro-1-([2′-{1H-tetrazol-5yl}biphenyl-4-yl]methyl)imidazole-5-carboxylate; EXP985, N-(2-[4-hydroxy-3-iodophenyl]ethyl)-4-chloro-2-propyl-1-([2′-{1H-tetrazol-5yl}biphenyl-4-yl]methyl)imidazole-5-carboxamide; irbesartan, 2-butyl-3-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one; L158809, 5, 7-dimethyl-2-ethyl-3-(2-[1H-tetrazol-5yl]biphe-nyl-4-yl)imidazo[4,5-b]pyridine; L162313, 5,7-dimethyl-2-ethyl-3-[[4-[2(n-butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazo[4,5,6]pyridine; losartan, 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole, also known as Dup 753; PD123177, 1-(4-amino-3-methylphenyl)methyl-3-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylate; PD123319, (S)-1-(4-[dimethylamino]-3-methylphenyl)methyl-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylate; valsartan, N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-L-valine

Further Reading

Aldigier JC, Ghannad E (2002). Exploring AT1 and AT2 angiotensin II receptors in humans. Drugs62: 11–19.

Bernstein KE, Marrero MB (1996). The importance of tyrosine phosphorylation in angiotensin II signaling. Trends Cardiovasc Med6: 179–187.

Carey RM (2005). Update on the role of the AT2 receptor. Curr Opin Nephrol Hypertens14: 67–71.

Cheung BM (2006). Therapeutic potential of angiotensin receptor blockers in hypertension. Expert Opin Investig Drugs15: 625–635.

De Gasparo M (2002). AT1 and AT2 angiotensin (II) receptors: key features. Drugs62: 1–10.

De Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T (2000). International Union of Pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev52: 415–472.

Ferrario CM, Chappell MC (2004). Novel angiotensin peptides. Cell Mol Life Sci61: 2720–2727.

Kusserow H, Unger T (2004). Vasoactive peptides, their receptors and drug development. Basic Clin Pharmacol Toxicol94: 5–12.

Maggioni AP (2006). Efficacy of angiotensin receptor blockers in cardiovascular disease. Cardiovasc Drugs Ther20: 295–308.

Nouet S, Nahmias C (2000). Signal transduction from the angiotensin II AT2 receptor. Trends Endocrinol Metab11: 1–6.

Rashid AJ, O'Dowd BF, George SR (2004). Minireview: diversity and complexity of signaling through peptidergic G protein-coupled receptors. Endocrinology145: 2645–2652.

Unger T (1999). The angiotensin type 2 receptor: variations on an enigmatic theme. J Hypertens17: 1775–1786.

Zaman MA, Oparil S, Calhoun DA (2002). Drugs targeting the renin-angiotensin-aldosterone system. Nat Rev Drug Discov1: 621–636.

References

Abdalla S et al. (2000). Nature407: 94–98.

Cappelli A et al. (2004). J Med Chem47: 2574–2586.

Lokuta AJ et al. (1995). J Biol Chem269: 4832–4838.

Moeller I et al. (1997). J Neurochem68: 2530–2537.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Apelin

Overview: The apelin receptor (APJ, provisional nomenclature previously designated as an orphan) responds to apelin, a 36 amino-acid peptide derived initially from bovine stomach. Apelin-36, apelin-13 and (Pyr1)apelin-13 are the predominant endogenous ligands which are cleaved from a 77 amino-acid precursor peptide (ENSG00000171388) by a so far unidentified enzymatic pathway (Tatemoto et al., 1998).

NomenclatureAPJ
Other namesApelin receptor, angiotensin receptor-like 1
Ensembl IDENSG00000134817
Principal transductionGi/o
Rank order of potency[Pyr1]apelin-13≥apelin-13>apelin-36 (Tatemoto et al., 1998; Fan et al., 2003)
Selective agonists[Pyr1]apelin-13, apelin-13, apelin-17, apelin-36
Probes[125I]-[Pyr1]Apelin-13 (0.3 nM, Katugampola et al., 2001), [125I]-apelin-13 (Fan et al., 2003), [3H]-[Pyr1][Met(0)11]apelin-13 (Medhurst et al., 2003), [125I]-[Nle75,Tyr77]apelin-36 (Kawamata et al., 2001)

Potency order determined for heterologously expressed human APJ receptor (pD2 values range from 9.5-8.6). APJ may also act as a co-receptor with CD4 for isolates of human immunodeficiency virus, with apelin blocking this function (Cayabyab et al., 2000). A modified apelin-13 peptide, apelin-13(F13A) was reported to block the hypotensive response to apelin in rat in vivo (Lee et al., 2005), however this peptide exhibits agonist activity in HEK293 cells stably expressing the recombinant APJ receptor (Fan et al., 2003).

Further Reading

Davenport AP, Pitkin SL, Maguire JJ (2007). Apelins. In Offermanns S, Rosenthal W (eds). Encyclopedic Reference of Molecular Pharmacology. Springer: Berlin.

Kleinz MJ, Davenport AP (2005). Emerging roles of apelin in biology and medicine. Pharmacol Ther107: 198–211.

Lee DK, George SR, O'Dowd BF (2006). Unravelling the roles of the apelin system: prospective therapeutic applications in heart failure and obesity. Trends Pharmacol Sci27: 190–194.

Maguire JJ, Davenport AP (2005). Regulation of vascular reactivity by established and emerging GPCRs. Trends Pharmacol Sci26: 448–454.

Masri B, Knibiehler B, Audigier Y (2005). Apelin signalling: a promising pathway from cloning to pharmacology. Cell Signal17: 415–426.

Sorli SC, van den Berghe L, Masri B, Knibiehler B, Audigier Y (2006). Therapeutic potential of interfering with apelin signalling. Drug Discov Today11: 1100–1106.

References

Cayabyab M et al. (2000). J Virol74: 11972–11976.

Fan X et al. (2003). Biochemistry42: 10163–10168.

Katugampola SD et al. (2001). Br J Pharmacol132: 1255–1260.

Kawamata Y et al. (2001). Biochim Biophys Acta1538: 162–171.

Lee DK et al. (2005). Endocrinology146: 231–236.

Medhurst AD et al. (2003). J Neurochem84: 1162–1172.

Tatemoto K et al. (1998). Biochem Biophys Res Commun251: 471–476.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Bile acid

Overview: The bile acid receptor (GPBA, provisional nomenclature) responds to bile acids produced during the liver metabolism of cholesterol.

NomenclatureGPBA
Other namesBG37, GPCR19, GPR131, M-BAR (Maruyama et al., 2002), MGC40597, TGR5 (Kawamata et al., 2003)
Ensembl IDENSG00000179921
Principal transductionGs (Maruyama et al., 2002)
Rank order of potencyLithocholic acid > deoxycholic acid > chenodeoxycholic acid, cholic acid (Maruyama et al., 2002; Kawamata et al., 2003)
Selective agonistsOleanolic acid (Sato et al., 2007)

Disruption of GPBA expression is reported to protect from cholesterol gallstone formation (Vassileva et al., 2006).

Further Reading

Houten SM, Watanabe M, Auwerx J (2006). Endocrine functions of bile acids. EMBO J25: 1419–1425.

References

Kawamata Y et al. (2003). J Biol Chem278: 9435–9440.

Maruyama T et al. (2002). Biochem Biophys Res Commun298: 714–719.

Sato H et al. (2007). Biochem Biophys Res Commun362: 793–798.

Vassileva G et al. (2006). Biochem J398: 423–430.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Bombesin

Overview: Bombesin receptors are activated by the endogenous ligands gastrin-releasing peptide (GRP), neuromedin B (NMB) and GRP-18-27 (previously named neuromedin C). Bombesin is a tetradecapeptide, originally derived from amphibians. These receptors couple, primarily, to the Gq/11 family of G proteins (but see also Jian et al., 1999). Activation of BB1 and BB2 receptors causes a wide range of physiological actions, including the stimulation of tissue growth, smooth-muscle contraction, secretion and many central nervous system effects (Tokita et al., 2002). A physiological role for the bb3 receptor has yet to be defined.

NomenclatureBB1BB2bb3
Other namesNMB-RGRP-RBRS-3
Ensembl IDENSG00000135577ENSG00000126010ENSG00000102239
Principal transductionGq/11Gq/11Gq/11
Selective agonistsNMBGRP
Selective antagonistsPD165929, dNal-cyc(Cys-Tyr-dTrp-Orn-Val)-Nal-NH2, dNal-Cys-Tyr-dTrp-Lys-Val-Cys-Nal-NH21-Naphthoyl-[dAla24, dPro26, Ψ26–27]GRP-20-27, kuwanon H, [dPhe6]bombesin-6-13-ethylester, [dPhe6, Cpa14, Ψ13–14]bombesin-6-14
Probes[125I]-BH-NMB, [125I]-[Tyr4]bombesin[125I]-[DTyr6]bombesin-6-13-methylester, [125I]-GRP, [125I]-[Tyr4]bombesin[125I]-[Tyr6, βAla11, Phe13, Nle14]bombesin-6-14

All three subtypes may be activated by [dPhe6, βAla11, Phe13, Nle14]bombesin-6-14 (Mantey et al., 1997). One analogue, [D-Tyr6, Apa-4Cl, Phe13, Nle14] bombesin-6-14, has more than 200-fold selectivity for bb3 receptors over BB1 and BB2 (Mantey et al., 2004).

Abbreviations: PD165929, 2-[3-(2,6-diisopropylphenyl)-ureido]3–(1H-indol-3-yl)-2-methyl-N-(1-pyridin-2-yl-cyclohexylmethyl)-proprionate

Further Reading

Battey J, Wada E (1991). Two distinct receptor subtypes for mammalian bombesin receptors. Trends Neurosci14: 524–528.

Iwabuchi M, Ui-Tei K, Yamada K, Matsuda Y, Sakai Y, Tanaka K et al. (2003). Molecular cloning and characterisation of avian bombesin-like peptide receptors: new tools for investigating molecular basis of ligand selectivity. Br J Pharmacol139: 555–566.

Jensen R, Coy D (1991). Progress in the development of potent bombesin receptor antagonists. Trends Pharmacol Sci12: 13–18.

Kroog GS, Jensen RT, Battey JF (1995). Bombesin receptors. Med Res Rev15: 389–417.

Moody TW, Merali Z (2004). Bombesin-like peptides and associated receptors within the brain: distribution and behavioural implications. Peptides25: 511–520.

Moody TW, Mantey SA, Pradhan TK, Schumann M, Nakagawa T, Martinez A et al. (2004). Development of high affinity camptothecin-bombesin conjugates that have targeted cytotoxicity for bombesin receptor-containing tumor cells. J Biol Chem279: 23580–23589.

Ohki-Hamazaki H (2000). Neuromedin B. Prog Neurobiol62: 297–312.

Ohki-Hamazaki H, Iwabuchi M, Maekawa F (2005). Development and function of bombesin-like peptides and their receptors. Int J Dev Biol49: 293–300.

Roesler R, Henriques JA, Schwartsmann G (2006). Gastrin-releasing peptide receptor as a molecular target for psychiatric and neurological disorders. CNS Neurol Disord Drug Targets5: 197–204.

Tokita K, Hocart SJ, Coy DH, Jensen RT (2002). Molecular basis of the selectivity of gastrin-releasing peptide receptor for gastrin-releasing peptide. Mol Pharmacol61: 1435–1443.

Weber D (2003). Design of selective peptidomimetic agonists for the human orphan receptor BRS-3. J Med Chem46: 1918–1930.

Zhou J, Chen J, Mokotoff M, Ball ED (2004). Targeting gastrin-releasing peptide receptors for cancer treatment. Anti-cancer Drugs15: 921–927.

References

Jian XY et al. (1999). J Biol Chem274: 11573–11581.

Mantey SA et al. (1997). J Biol Chem272: 26062–26071.

Mantey SA et al. (2004). J Pharmacol Exp Ther310: 1161–1170.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1-S209.

Bradykinin

Overview: Bradykinin (or kinin) receptors (nomenclature recommended by the NC-IUPHAR Subcommittee on bradykinin (kinin) receptors, Leeb-Lundberg et al., 2005) are activated by the endogenous peptides bradykinin (BK), [des-Arg9]BK, Lys-BK (kallidin), Lys-[des-Arg9]BK, T-kinin (Ile-Ser-BK), [Hyp3]BK and Lys-[Hyp3]BK. The variation in affinity or inactivity of B2 receptor antagonists could reflect the existence of species homologues of B2 receptors.

NomenclatureB1B2
Ensembl IDENSG00000100739ENSG00000168398
Principal transductionGq/11Gq/11
Rank order of potencyLys-[des-Arg9]BK> [des-Arg9]BK = Lys-BK> BKLys-BK≥BK> > [des-Arg9]BK, Lys-[des-Arg9]BK
Selective agonistsLys-[des-Arg9]BK, Sar[DPhe8][des-Arg9]BK[Phe8,Ψ(CH2-NH)Arg9]BK, [Hyp3,Tyr(Me)8]BK
Selective antagonistsB9958 (9.2, Regoli et al., 1998), R914 (8.6, Gobeil et al., 1999), R715 (8.5, Gobeil et al., 1996a), Lys-[Leu8][des-Arg9]BK (8.0)Icatibant (8.4, Gobeil et al., 1996b), FR173657 (8.2, Rizzi et al., 1997), LF160687 (Pruneau et al., 1999)
Probes[3H]-Lys-[des-Arg9]BK (0.4 nM), [3H]-Lys-[Leu8][des-Arg9]BK, [125I]-Hpp-desArg9HOE140 (0.1 nM)[3H]-BK (0.2 nM), [3H]-NPC17731 (50–900 pM), [125I]-[Tyr8]BK

Abbreviations: B9958, Lys-Lys[Hyp3,Cpg5,dTic7,Cpg8][des-Arg9]BK; FR173657, (E)-3-(6-acetamido-3-pyridyl)-N-(N-[2,4-dichloro-3{(2-methyl-8-quinolinyl)oxymethyl} phenyl]-N-methylaminocarbonyl-methyl)acrylamide; Icatibant, DArg[Hyp3,Thi5,DTic7,Oic8]BK,also known as HOE140 LF160687, 1-([2,4-dichloro-3-{([2,4-dimethylquinolin-8-yl]oxy)methyl}phenyl]sulfonyl)-N-(3-[{4-(aminoimethyl)phenyl}carbonylamino]propyl)-2(S)-pyrrolidinecarboxamide; NPC17731, DArg[Hyp3,DHypE(transpropyl)7,Oic8]BK; R715, AcLys[D Nal7,Ile8][des-Arg9]BK; R914, AcLys-Lys-([αMe]Phe5δ-βNal7,Ile8)desArg9BK

Further Reading

Calixto JB, Medeiros R, Fernandes ES, Ferreira J, Cabrini DA, Campos MM (2004). Kinin B1 receptors: key G-protein-coupled receptors and their role in inflammatory and painful processes. Br J Pharmacol143: 803–818.

Campos MM, Leal PC, Yunes RA, Calixto JB (2006). Non-peptide antagonists for kinin B1 receptors: new insights into their therapeutic potential for the management of inflammation and pain. Trends Pharmacol Sci27: 646–651.

Couture R, Harrison M, Vianna RM, Cloutier F (2001). Kinin receptors in pain and inflammation. Eur J Pharmacol429: 161–176.

Doggrell SA (2006). Bradykinin B2 receptors as a target in diabetic nephropathy. Curr Opin Investig Drugs7: 251–255.

Fortin JP, Marceau FO (2006). Advances in the development of bradykinin ligands. Curr Top Med Chem6: 1353–1363.

Leeb-Lundberg LMF, Marceau F, Muller-Esterl W, Pettibone DJ, Zuraw BL (2005). International Union of Pharmacology. XLV. Classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences. Pharmacol Rev57: 27–77.

Marceau F, Hess JF, Bachvarov DR (1998). The B-1 receptors for kinins. Pharmacol Rev50: 357–386.

Marceau F, Regoli D (2004). Bradykinin receptor ligands: Therapeutic perspectives. Nature Rev Drug Discov3: 845–852.

Regoli D, Allogho SN, Rizzi A, Gobeil FJ (1998). Bradykinin receptors and their antagonists. Eur J Pharmacol348: 1–10.

Rodi D, Couture R, Ongali B, Simonato M (2005). Targeting kinin receptors for the treatment of neurological diseases. Curr Pharm Des11: 1313–1326.

References

Gobeil F et al. (1996a). Hypertension28: 833–839.

Gobeil F et al. (1996b). Br J Pharmacol118: 289–294.

Gobeil F et al. (1999). Hypertension33: 823–829.

Pruneau D et al. (1999). Immunopharmacology43: 187–194.

Rizzi A et al. (1997). Hypertension29: 951–956.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1-S209.

Calcitonin, amylin, CGRP and adrenomedullin

Overview: Calcitonin (CT), amylin (AMY), calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on CGRPs, AM, AMY, and CT receptors, see Poyner et al., 2002) are generated by the genes CALCR (which codes for the CT receptor) and CALCRL (which codes for the calcitonin receptor-like receptor, CL receptor, previously known as CRLR), whose function and pharmacology are altered in the presence of RAMPs (receptor activity-modifying protein). RAMPs are single TM domain proteins of ca. 130 amino acid, identified as a family of three members; RAMP1 (ENSG00000132329), RAMP2 (ENSG00000131477) and RAMP3 (ENSG00000122679). There are splice variants of the CT receptor; these in turn produce variants of the AMY receptor (see Poyner et al., 2002) The endogenous agonists are the peptides CT, αCGRP (also known as CGRP-I), βCGRP (also known as CGRP-II), AMY (also known as islet-amyloid polypeptide, diabetes-associated polypeptide) and AM. There are species differences in peptide sequences, particularly for the CTs. AM2/Intermedin (AM2/IMD) can also activate CGRP1, AM1, AM2 and AMY1 receptors, albeit less potently than the cognate agonists (Ogoshi et al., 2003; Roh et al., 2004; Hay et al., 2005). CT receptor-stimulating peptide (CRSP) is another member of the family with selectivity for the CT receptor; it has not been found in humans (Katafuchi et al., 2003). BIBN4096BS is the most selective antagonist available, having a high selectivity for CGRP1 receptors, with a particular preference for those of primate origin. CGRP-(8-37) acts as an antagonist of CGRP (pKi 6.5–8.0) and inhibits some AM and AMY responses (7.0). It is inactive at CT receptors. Salmon calcitonin-(8-32) is an antagonist at both amylin and CT receptors. AC187, a salmon CT analogue, is also an antagonist at amylin and CT receptors. Human AM-(22-52) has some selectivity towards AM receptors, but with modest potency, limiting its use.

NomenclatureCalcitoninAmylinCGRPAdrenomedullin
CompositionCALCRAMY1: CALCR+RAMP1 AMY2: CALCR+RAMP2 AMY3: CALCR+RAMP3CGRP1: CALCRL+RAMP1AM1: CALCRL+RAMP2 AM2: CALCRL+RAMP3
Ensembl IDENSG00000004948ENSG00000064989
Principal transductionGs/GqGsGs/GqGs
Rank order of potencySalmon CT>human CT>AMY, CGRP>AM, AM2/IMDAMY1a: Salmon CT>AMY>CGRP>AM2/IMD>human CT>AM AMY3a: Salmon CT>AMY>CGRP>AM2/IMD>human CT>AMCGRP>AM>AM2/IMD>AMY>salmon CTAM1: AM>>CGRP, AM2/IMD>AMY>salmon CT AM2: AM>CGRP, AM2/IMD>AMY>salmon CT
Selective agonistsHuman CTAMYαCGRPAM
Selective antagonistsBIBN4096BS (11, Doods et al., 2000; Hay et al., 2003, 2006)AM-(22-52) (7)
Probes[125I]-CT (salmon, 0.1 nM), [125I]-CT (human, 0.1–1.0 nM)[125I]-BH-AMY (rat, 0.1–1.0 nM)[125I]-αCGRP (0.1 nM)[125I]-AM (rat, 0.1–1.0 nM)

The agonists described represent the best available but their selectivity is limited. AM has appreciable affinity for CGRP receptors and some of its effects can be antagonised by CGRP-(8-37). CGRP can show significant cross-reactivity at amylin receptors and some AM receptors. Responsiveness to human CT can be affected by splice variation (at the rat C1b receptor it is very weak, Houssami et al., 1994). Particularly for AMY receptors, relative potency can vary with the type and level of RAMP present and can be influenced by other factors such as G-proteins (Tilakaratne et al., 2000).

Gs is a prominent route for effector coupling but other pathways (e.g. Ca2+ and nitric oxide) and G-proteins can be activated. The coupling can be affected by splice variants of the CT receptor (e.g. the 490 amino-acid form of the human receptor, CT(b), does not cause an increase in intracellular Ca2+ and might have low efficacy in generating cAMP).

There is evidence that CGRP-RCP (a 148 amino-acid hydrophilic protein, ENSG00000126522) is important for the coupling of the CL receptor to adenylyl cyclase (Evans et al., 2000). When co-expressed with RAMP2, the CL receptor produces an AM receptor (AM1). RAMP3 interacts with the CL receptor to give another receptor that is responsive to AM (AM2, Fraser et al., 1999). There is some evidence that these AM receptors are pharmacologically distinct (Hay et al., 2003). Transfection of hCT(a) with any RAMP can give a receptor with a high affinity for both salmon CT and AMY and varying affinity for different antagonists (Christopoulos et al., 1999; Hay et al., 2005, 2006). hCT(a)—RAMP1 has a high affinity for CGRP, unlike hCT(a)—RAMP3 (Christopoulos et al., 1999; Hay et al., 2005). However, AMY receptor phenotype is RAMP-type- and cell-line-dependent (Tilakaratne et al., 2000).

[125I]-Salmon calcitonin is the most common radioligand for calcitonin receptors but it has high affinity for amylin receptors and is also poorly reversible. [125I]-Tyr0-CGRP is widely used as a radioligand for CGRP receptors.

CGRP1 and CGRP2 subtypes have been proposed on the basis of the action of the agonists [Cys(ACM)2,7]CGRP or [Cys(Et)2,7]CGRP (putative CGRP2-selective agents) and antagonist CGRP-(8-37) (CGRP1-selective, pki 7.0–8.0, Juaneda et al., 2000). CL/RAMP1 represents the CGRP1 subtype previously described in native tissues and cell lines (Aiyar et al., 1996; McLatchie et al., 1998). There is not yet a clear molecular correlate for the CGRP2 receptor, although in some cases it may represent CGRP acting via AM2 or amylin receptors.

Abbreviations: AC187, acetyl-[Asn30, Tyr32]salmon CT; AM2/IMD, AM2/intermedin; BIBN409BS, 1-piperidinecarboxamide, N-(2-[{5–amino-1-([4-{4-pyridinyl}-1-piperazinyl]carbonyl)pentyl}amino]-1-[{3,5–dibromo-4-hydroxyphenyl}methyl]-2-oxoethyl)-4-(1,4-dihydro-2-oxo-3[2H]-quinazolinyl); [Cys(ACM)2,7]CGRP, [acetamidomethyl-Cys2,7]CGRP; [Cys(Et)2,7]CGRP, [ethylamide-Cys2,7]CGRP

Further Reading

Brain SD, Cox HM (2006). Neuropeptides and their receptors: innovative science providing novel therapeutic targets. Br J Pharmacol147: S202-S211.

Brain SD, Grant AD (2004). Vascular actions of calcitonin gene-related peptide and adrenomedullin. Physiol Rev84: 903–934.

Durham PL (2004). CGRP receptor antagonists: a new choice for acute treatment of migraine? Curr Opin Investig Drugs5: 731–735.

Garcia MA, Martin-Santamaria S, de Pascual-Teresa B, Ramos A, Julian M, Martinez A (2006). Adrenomedullin: a new and promising target for drug discovery. Expert Opin Ther Targets10: 303–317.

Gibbons C, Dackor R, Dunworth W, Fritz-Six K, Caron KM (2007). Receptor activity-modifying proteins: RAMPing up adrenomedullin signaling. Mol Endocrinol21: 783–796.

Hay DL (2007). What makes a CGRP2 receptor? Clin Exp Pharmacol Physiol34: 963–971.

Hay DL, Poyner DR, Sexton PM (2006). GPCR modulation by RAMPs. Pharmacol Ther109: 173–197.

Ishimitsu T, Ono H, Minami J, Matsuoka H (2006). Pathophysiologic and therapeutic implications of adrenomedullin in cardiovascular disorders. Pharmacol Ther111: 909–927.

Lipton RB, Dodick DW (2004). CGRP antagonists in the acute treatment of migraine. Lancet Neurol3: 332–33.

Nikitenko LL, Fox SB, Kehoe S, Rees MC, Bicknell R (2006). Adrenomedullin and tumour angiogenesis. Br J Cancer94: 1–7.

Poyner DR, Sexton PM, Marshall I, Smith DM, Quirion R, Born W et al. (2002). International union of pharmacology. XXXII. The Mammalian Calcitonin gene-related peptides, Adrenomedullin, Amylin, and Calcitonin receptors. Pharmacol Rev54: 233–246.

References

Aiyar N et al. (1996). J Biol Chem271: 11325–11329.

Christopoulos G et al. (1999). Mol Pharmacol56: 235–242.

Doods H et al. (2000). Br J Pharmacol129: 420–423.

Evans BN et al. (2000). J Biol Chem275: 31438–31443.

Fraser NJ et al. (1999). Mol Pharmacol55: 1054–1059.

Hay DL et al. (2003). Br J Pharmacol140: 477–486.

Hay DL et al. (2005). Mol Pharmacol67: 1655–1665.

Hay DL et al. (2006). Mol Pharmacol70: 1984–1991.

Houssami S et al. (1994). Endocrinology135: 183–190.

Juaneda C et al. (2000). Trends Pharmacol Sci21: 432–438.

Katafuchi T et al. (2003). J Biol Chem278: 12046–12054.

McLatchie LM et al. (1998). Nature393: 333–339.

Ogoshi M et al. (2003). Biochem Biophys Res Commun311: 1072–1077.

Roh J et al. (2004). J Biol Chem279: 7264–7274.

Tilakaratne N et al. (2000). J Pharmacol Exp Ther294: 61–72.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1-S209.

Calcium-sensing

Overview: The calcium-sensing receptor (CaR, provisional nomenclature) responds to extracellular calcium and magnesium in the millimolar range and to gadolinium and some polycations in the micromolar range (Brown et al., 1993). The sensitivity of CaR to primary agonists can be increased by aromatic L-amino acids (Conigrave et al., 2000) and also by a rise in extracellular pH (Quinn et al., 2004).

NomenclatureCaR
Other namesParathyroid cell calcium-sensing receptor, CASR
Ensembl IDENSG00000036828
Principal transductionGq/11, Gi/o, G12/13 (Ward et al., 2004)
Cation rank order of potencyGd3+>Ca2+>Mg2+ (Brown et al., 1993)
Polyamine rank order of potencySpermine>spermidine>putrescine (Quinn et al., 1997)
Amino-acid rank order of potencyL-Phe, L-Trp, L-His>L-Ala>L-Ser, L-Pro, L-Glu>L-Asp but not L-Lys, L-Arg, L-Leu, and L-Ile (Conigrave et al., 2000)
Positive allosteric modulatorsNPS R568 (Nemeth et al., 1998), calindol (Petrel et al., 2004), cinacalcet (Nemeth et al., 2004)
Negative allosteric modulatorsNPS 2143, NPS 89636 (Nemeth et al., 2001), Calhex-231 (Petrel et al., 2004), 2-benzylpyrrolidine derivatives of NPS 2143 (Yang et al., 2005)

Positive allosteric modulators are termed Type II calcimimetics and can suppress parathyroid hormone secretion (Nemeth et al., 1998). Negative allosteric modulators are called calcilytics and can act to increase parathyroid hormone secretion (Nemeth et al., 2001).

The central role of CaR in the maintenance of extracellular calcium homeostasis is seen most clearly in patients with loss-of-function CaR mutations who develop familial hypocalciuric hypercalcaemia (heterozygous mutation) or neonatal severe hyperparathyroidism (homozygous mutation) and in CaR null mice (Ho et al., 1995), which exhibit similar increases in PTH secretion and blood Ca2+ levels. A gain-of-function mutation in the CaR gene is associated with autosomal dominant hypocalcaemia.

Abbreviations: Calhex-231, (1S,2S,1′R)-N1-(4-chlorobenzoyl)-N2-[1-(1-naphthyl)ethyl]-1,2-diaminocyclohexane; calindol, (R)-2-[1-(1-naphthyl) ethylaminomethyl]-1H-indole; NPS 2143,N-[(R)-2-hydroxy-3-(2-cyano-3-chlorophenoxy)propyl]-1,1-dimethyl-2-(2-naphthyl)ethylamine; NPS R568, (R)-N-(3-methoxy-ω-phenylethyl)-3-(2-chlorophenyl)-1-propylamine hydrochloride

Further Reading

Brown EM (2007). Clinical lessons from the calcium-sensing receptor. Nat Clin Pract Endocrinol Metab3: 122–133.

Chattopadhyay N (2006). Effects of calcium-sensing receptor on the secretion of parathyroid hormone-related peptide and its impact on humoral hypercalcemia of malignancy. Am J Physiol Endocrinol Metab290: E761-E770.

Conigrave AD, Brown EM (2006). Taste receptors in the gastrointestinal tract. II. L-amino acid sensing by calcium-sensing receptors: implications for GI physiology. Am J Physiol Gastrointest Liver Physiol291: G753-G761.

Conigrave AD, Hampson DR (2006). Broad-spectrum L-amino acid sensing by class 3 G-protein-coupled receptors. Trends Endocrinol Metab17: 398–407.

Hebert SC (2006). Therapeutic use of calcimimetics. Annu Rev Med57: 349–364.

Nagano N, Nemeth EF (2005). Functional proteins involved in regulation of intracellular Ca2+ for drug development: the extracellular calcium receptor and an innovative medical approach to control secondary hyperparathyroidism by calcimimetics. J Pharmacol Sci97: 355–360.

Steddon SJ, Cunningham J (2005). Calcimimetics and calcilytics—fooling the calcium receptor. Lancet365: 2237–2239.

References

Brown EM et al. (1993). Nature366: 575–580.

Conigrave AD et al. (2000). Proc Natl Acad Sci USA97: 4814–4819.

Ho C et al. (1995). Nat Genet11: 389–394.

Nemeth EF et al. (1998). Proc Natl Acad Sci USA95: 4040–4045.

Nemeth EF et al. (2001). J Pharmacol Exp Ther299: 323–331.

Nemeth EF et al. (2004). J Pharmacol Exp Ther308: 627–635.

Petrel C et al. (2004). J Biol Chem279: 18990–18997.

Quinn SJ et al. (1997). Am J Physiol -Cell Physiol273: C1315-C1323.

Quinn SJ et al. (2004). J Biol Chem279: 37241–37249.

Ward DT (2004). Cell Calcium35: 217–228.

Yang W et al. (2005). Bioorg Med Chem Lett15: 1225–1228.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1-S209.

Cannabinoid

Overview: Cannabinoid receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Cannabinoid Receptors; see Howlett et al., 2002) are activated by endogenous ligands that include N-arachidonoylethanolamine (anandamide), N-homo-γ-linolenoylethanolamine, N-docosatetra-7,10,13,16-enoylethanolamine and 2-arachidonoylglycerol. Potency determinations are complicated by the possibility of differential susceptibility of endogenous ligands to enzymatic conversion (see Alexander and Kendall, 2007). Both CB1 and CB2 receptors may be labelled with [3H]-CP55940 (0.6 nM; Showalter et al., 1996) and [3H]-WIN55212-2 (2–12 nM; Slipetz et al., 1995; Song and Bonner, 1996).

Further cannabinoid-like receptors have been described, including GPR55 (ENSG00000135898), which appears to respond to a wide spectrum of cannabinoid agonists and antagonists (see Brown, 2007; Pertwee, 2007; Ryberg et al., 2007). GPR18 has been described to be a 7-transmembrane receptor for N-arachidonoylglycine (Kohno et al., 2006), while GPR119 responds to fatty acid ethanolamides (N-oleoylethanolamine>N-palmitoylethanolamine>anandamide; Overton et al., 2006). Synthetic agonists for this receptor include PSN375963 and PSN632408 (Overton et al., 2006). Other pharmacological targets for cannabinoids have also been proposed (see Baker et al., 2006; Begg et al., 2005; Pertwee, 2005a).

NomenclatureCB1CB2
Ensembl IDENSG00000118432ENSG00000162562
Principal transductionGi/oGi/o
Selective agonistsACEA (Hillard et al., 1999), ACPA (Hillard et al., 1999), methanandamide (Khanolkar et al., 1996), O1812 (Di Marzo et al., 2001)HU308 (Hanus et al., 1999), JWH133 (Huffman et al., 1999; Pertwee, 2000), L759633 (Ross et al., 1999), L759656 (Ross et al., 1999), AM1241 (Ibrahim et al., 2003)
Selective antagonistsAM251 (8.1, Lan et al., 1999a), AM281 (7.9, Lan et al., 1999b) rimonabant (7.9, Showalter et al., 1996), LY320135 (6.9, Felder et al., 1998)SR144528 (9.2, Rinaldi-Carmona et al., 1998), AM630 (7.5, Ross et al., 1999)
Probes[3H]-rimonabant (0.6 nM, Rinaldi-Carmona et al., 1996)

Anandamide is also an agonist at vanilloid receptors (TRPV1) and PPARs (see O'Sullivan, 2007; Zygmunt et al., 1999). There is evidence for an allosteric site on the CB1 receptor (Price et al., 2005). All of the compounds listed as antagonists behave as inverse agonists in some bioassay systems (see Pertwee, 2005a, b).

Abbreviations: ACEA, arachidonoyl-2-chloroethylamide; ACPA, arachidonoylcyclopropylamide; AM1241, (2-iodo-5-nitro-phenyl)-[1-(1-methyl-piperidin-2-ylmethyl)-1H-indol-3-yl]-methanone; AM251,N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide; AM281, 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide; AM630, 6-iodopravadoline; CP55940, (1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl) phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol; HU308, {4-[4-(1,1-dimethylheptyl)-2,6-dimethoxy-phenyl]-6,6-dimethyl-bicyclo[3.1.1]hept-2-en-2-yl}-methanol; JWH133, (3-(1,1-dimethylbutyl)-6,6,9-tri-methyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene; L759633, (6ar,10ar)-3-(1,1-dimethylheptyl)-1-methoxy-6,6,9-trimethyl-6a,7,10,10a-tetra-hydro-6H-benzo[c]chromene; L759656, (6ar,10ar)-3-(1,1-dimethylheptyl)-1-methoxy-6,6-dimethyl-9-methylene-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromene; LY320135, (6-methoxy-2-[4-methoxyphenyl]benzo[b]thien-3-yl)(4-cyanophenyl)methanone; methanandamide, (R)-(+)-arachidonoyl-1′-hydroxy-2′-propylamide; O1812, (R)-(20-cyano-16,16-dimethyldocosa-cis-5,8,11,14-tetraenoyl)-1′-hydroxy-2′-propyl-amine; PSN375963, 4-(5-[4-butylcyclohexyl]-1,2,4-oxadiazol-3-yl)pyridine; PSN632408, 4-([3-{4-pyridinyl}-1,2,4-oxadiazol-5-yl]methoxy)-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester; rimonabant,N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride, also known as SR141716A; SR144528,N-([1S]-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide; WIN55212-2, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)-pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate

Further Reading

Alexander SPH, Kendall DA (2007). The complications of promiscuity: endocannabinoid action and metabolism. Br J Pharmacol152: 602–623.

Baker D, Pryce G, Davies WL, Hiley CR (2006). In silico patent searching reveals a new cannabinoid receptor. Trends Pharmacol Sci27: 1–4.

Begg M, Pacher P, Batkai S, Osei-Hyiaman D, Offertaler L, Mo FM et al. (2005). Evidence for novel cannabinoid receptors. Pharmacol Ther106: 133–145.

Brown AJ (2007). Novel cannabinoid receptors. Br J Pharmacol152: 567–575.

Centonze D, Finazzi-Agro A, Bernardi G, Maccarrone M (2007). The endocannabinoid system in targeting inflammatory neurodegenerative diseases. Trends Pharmacol Sci28: 180–187.

Di Marzo V, Bisogno T, De Petrocellis L (2007). Endocannabinoids and related compounds: walking back and forth between plant natural products and animal physiology. Chem Biol14: 741–756.

Di Marzo V, De Petrocellis L (2006). Plant, synthetic, and endogenous cannabinoids in medicine. Annu Rev Med57: 553–574.

Di Marzo V, Petrosino S (2007). Endocannabinoids and the regulation of their levels in health and disease. Curr Opin Lipidol18: 129–140.

Fernandez-Ruiz J, Romero J, Velasco G, Tolon RM, Ramos JA, Guzman M (2007). Cannabinoid CB2 receptor: a new target for controlling neural cell survival? Trends Pharmacol Sci28: 39–45.

Fowler CJ (2006). The cannabinoid system and its pharmacological manipulation—a review, with emphasis upon the uptake and hydrolysis of anandamide. Fundam Clin Pharmacol20: 549–562.

Harkany T, Guzman M, Galve-Roperh I, Berghuis P, Devi LA, Mackie K (2007). The emerging functions of endocannabinoid signaling during CNS development. Trends Pharmacol Sci28: 83–92.

Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA et al. (2002). International Union Of Pharmacologyw. XXVII. Classification of cannabinoid receptors. Pharmacol Rev54: 161–202.

Lever IJ, Rice AS (2007). Cannabinoids and pain. Handb Exp Pharmacol177: 265–306.

Mackie K (2006). Cannabinoid receptors as therapeutic targets. Annu Rev Pharmacol Toxicol46: 101–122.

McPartland JM, Glass M, Pertwee RG (2007). Meta-analysis of cannabinoid ligand binding affinity and receptor distribution: interspecies differences. Br J Pharmacol152: 583–593.

O'Sullivan SE (2007). Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors. Br J Pharmacol152: 583–593.

Pertwee RG (2005a). Pharmacological actions of cannabinoids. Handb Exp Pharmacol168: 1–51.

Pertwee RG (2005b). Inverse agonism and neutral antagonism at cannabinoid CB1 receptors. Life Sci76: 1307–1324.

Pertwee RG (2006). Cannabinoid pharmacology: the first 66 years. Br J Pharmacol147: S163-S171.

Pertwee RG (2006). The pharmacology of cannabinoid receptors and their ligands: an overview. Int J Obes (Lond)30: S13-S18.

Pertwee RG (2007). GPR55: a new member of the cannabinoid receptor clan? Br J Pharmacol152: 984–986.

Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson N-O, Leonova J et al. (2007). The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol152: 1092–1101.

Sugiura T, Kishimoto S, Oka S, Gokoh M (2006). Biochemistry, pharmacology and physiology of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand. Prog Lipid Res45: 405–446.

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Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1-S209.

Chemokine

Overview: Chemokine receptors (nomenclature agreed by NC-IUPHAR Subcommittee on Chemokine Receptors, Murphy et al., 2000; Murphy, 2002) comprise a large subfamily of 7TM receptors activated by one or more of the chemokines, a large family of small cytokines typically possessing chemotactic activity for leukocytes.

Chemokines can be divided by structure into four subclasses by the number and arrangement of conserved cysteines. CC (also known as α-chemokines; n=28), CXC (also known as α-chemokines; n=16) and CX3C (n= 1) chemokines all have four conserved cysteines, with zero, one and three amino acids separating the first two cysteines, respectively. C chemokines (n= 2) have only the second and fourth cysteines found in other chemokines. Chemokines can also be classified by function into homeostatic and inflammatory subgroups. Most chemokine receptors are able to bind multiple high affinity chemokine ligands, but the ligands for a given receptor are almost always restricted to the same structural subclass. Most chemokines bind to more than one receptor subtype. Receptors for inflammatory chemokines are typically highly promiscuous with regard to ligand specificity, and may lack a selective endogenous ligand. Listed are those human agonists with EC50 values <50 nM in either Ca2+ flux or chemotaxis assays at human recombinant receptors expressed in mammalian cell lines. There can be substantial cross-species differences in the sequences of both chemokines and chemokine receptors, and in the pharmacology and biology of chemokine receptors. Endogenous and HIV-encoded non-chemokine ligands have also been identified for chemokine receptors. Many chemokine receptors function as HIV co-receptors, and at least two, CCR5 and CXCR4, play prominent roles in pathogenesis. The tables include both standard chemokine names (Zlotnik and Yoshie, 2000) and the most commonly used synonyms. Numerical data quoted are typically pKi or pIC50 values from radioligand binding to heterologously expressed receptors.

NomenclatureCCR1CCR2CCR3CCR4CCR5
Other namesCKR1, CC CK1, CC CKR1, MIP-1αR, MIP-1α/RANTESCKR2, CC CK2, CC CKR2, MCP-1CKR3, CC CK3, CC CKR3CKR4, CC CK4, CC CKR4CKR5, CC CK5, CC CKR5, CHEMR13
Ensembl IDENSG00000163823ENSG00000121807ENSG00000183625ENSG00000183813ENSG00000160791
Principal transductionGi/oGi/oGi/oGi/oGi/o
AgonistsCCL3 (MIP-1α), CCL5 (RANTES), CCL7 (MCP-3), CCL8 (MCP-2), CCL13 (MCP-4), CCL14a (HCC-1), CCL15 (HCC-2), CCL23 (MPIF-1)CCL2 (MCP-1), CCL7 (MCP-3), CCL8 (MCP-2), CCL13 (MCP-4), CCL16 (HCC-4), HIV-1 TatCCL11 (eotaxin), CCL5 (RANTES), CCL7 (MCP-3), CCL8 (MCP-2), CCL13 (MCP-4), CCL15 (HCC-2), CCL24 (eotaxin-2), CCL26 (eotaxin-3), CCL28 (MEC), HIV-1 TatCCL22 (MDC), CCL17 (TARC), HHV8 vMIP-III,CCL3 (MIP-1α), CCL4 (MIP-1β), CCL5 (RANTES), CCL8 (MCP-2), CCL11 (eotaxin), CCL14a (HCC-1), CCL16 (HCC-4), R5 HIV-1 gp120
Selective agonistsCCL15 (HCC-2), CCL23 (MPIF-1)CCL2 (MCP-1)CCL11 (Eotaxin), CCL24 (eotaxin-2), CCL26 (eotaxin-3),CCL22 (MDC), CCL17 (TARC)MIP-1β, R5-HIV gp120
Selective antagonistsBX471 (8.3-9), 2b-1 (8.7), UCB35625 (8.0), CP-481,715 (8.0), CCL4 (MIP-1β)CCL11 (eotaxin), CCL26 (eotaxin-3), GSK Compound 34 (7.6)Banyu Compound 1b (8.6), SB328437 (8.4), BMS Compound 87b (8.1), CXCL10 (IP10), CXCL9 (Mig), CXCL11 (I-TAC)TAK779 (9.0), CCL7 (MCP-3), SCH C, SCH D, MRK-1, E913 (8.7), maraviroc, aplaviroc
Probes[125I]-MIP-1α, [125I]-RANTES, [125I]-MCP-3[125I]-MCP-1, [125I]-MCP-3[125I]-RANTES, [125I]-eotaxin, [125I]-MCP-3[125I]-TARC, [125I]-CTACK/CCL27[125I]-RANTES, [125I]-MCP-2, [125I]-MIP-1α, [125I]-MIP-1β
NomenclatureCCR6CCR7CCR8CCR9CCR10
Other namesGPR-CY4, CKR-L3, STRL-22, DRY-6, DCR2, BN-1, GPR29EBI-1, BLR-2TER1, CKR-L1, GPR-CY6, ChemR1GPR 9-6GPR-2
Ensembl IDENSG00000153467ENSG00000126353ENSG00000179934ENSG00000173585ENSG00000184451
Principal transductionGi/oGi/oGi/oGi/oGi/o
AgonistsCCL20 (LARC), HBD2CCL19 (ELC, MIP-3β), CCL21 (SLC)CCL1 (I-309), CCL4 (MIP-1β), CCL16 (HCC-4), CCL17 (TARC), HHV8 vMIP-ICCL25 (TECK)CCL27 (Eskine, ALP, CTACK), CCL28 (MEC)
Selective agonistsLARC, HBD2ELC, SLCI-309TECKEskine, MEC
Selective antagonistsMCV MC148R (vMCC-I)
Probes[125I]-LARC[125I]-ELC, [125I]-SLC[125I]-I309[125I]-TECK 
NomenclatureCXCR1CXCR2CXCR3CXCR4CXCR5CXCR6
Other namesIL8RA, IL-8 receptor type I, IL-8 receptor αIL8RB, IL-8 receptor type II, IL-8 receptor βIP10/Mig R, GPR9HUMSTSR, LESTR, fusin, HM89, LCR1BLR-1, MDR15STRL-33, BONZO, TYMSTR
Ensembl IDENSG00000163464 ENSG00000172215ENSG00000180871SwissProt P49682ENSG00000121966ENSG00000160683 
Principal transductionGi/oGi/oGi/oGi/oGi/oGi/o
AgonistsCXCL6 (GCP-2), CXCL8 (IL-8), cytokine domain of tyrosyl tRNA synthetaseCXCL1 (GROα), CXCL2 (GROβ), CXCL3 (GROγ), CXCL5 (ENA-78), CXCL6 (GCP-2), CXCL7 (NAP-2), CXCL8 (IL-8), HCMV UL146 (vCXC-1)CXCL9 (Mig), CXCL10 (IP10), CXCL11 (I-TAC)CXCL12α & β (SDF-1α, SDF-1β)CXCL13 (BLC, BCA-1)CXCL16 (SR-PSOX)
Selective agonistsGROα, GROγ, GROβ, NAP-2, ENA78IP10, MIG, I-TACSDF-1α, SDF-1β, X4-HIV gp120BLCCXCL16
Selective antagonistsSB225002 (7.7)eotaxin, MCP-3AMD3100, HIV-1 Tat, T134, ALX41-4C
Probes [125I]-IL8[125I]-IL8, [125I]-GROα, [125I]-NAP-2, [125I]-ENA78[125I]-IP10, [125I]-I-TAC/CXCL11[125I]-SDF-1[125I]-CXCL16 

CXCR1 and CXCR2 also couple to phospholipase C when co-transfected with members of the Gq/11 family of G proteins. Mouse CXCR2 binds iodinated mouse KC and mouse MIP-2 with high affinity (mouse KC and MIP-2 are homologues of human GRO chemokines), but shows low affinity for human IL-8.

NomenclatureCX3CR1XCR1
Other namesCMKBRL1, V28GPR5
Ensembl IDENSG00000168329ENSG00000173578
Principal transductionGi/oGi/o
AgonistsCX3CL1 (Fractalkine)XCL1 α and β(Lymphotacin α and β)
Selective agonistsFractalkineLymphotactin
Probes[125I]-FractalkineSEAP-XCL1

Three human 7TM chemokine binding proteins have been identified that lack a known signalling function: D6 (ENSG00000144648), which binds multiple CC chemokines; a molecule previously inappropriately named CCR11 and now known as CCX CKR or the human homolog of the bovine gustatory receptor PPAR1 (ENSG00000118519, ENSG00000129048), which binds ELC, SLC and TECK; and Duffy, a highly promiscuous CC and CXC chemokine binding protein expressed mainly on erythrocytes. Specific chemokine receptors facilitate cell entry by microbes, such as Plasmodium vivax, HIV-1 and the poxvirus myxoma virus. Virally encoded chemokine receptors are known (e.g. US28, a homologue of CCR1 from human cytomegalovirus and ECRF3, a homologue of CXCR2 from Herpesvirus saimiri), but their role in viral life cycles is not established. Viruses can exploit or subvert the chemokine system by producing chemokine antagonists and scavengers.

The CC chemokine family (CCL1–28) includes I309 (CCL1), MCP-1 (CCL2), MIP-1α (CCL3), MIP-1β (CCL4), RANTES (CCL5), MCP-3 (CCL7), MCP-2 (CCL8), eotaxin (CCL11), MCP-4 (CCL13), HCC-1 (CCL14), Lkn-1/HCC-2 (CCL15), TARC (CCL17), ELC (CCL19), LARC (CCL20), SLC (CCL21), MDC (CCL22), MPIF-1 (CCL23), eotaxin-2 (CCL24), TECK (CCL25), eotaxin (CCL26), eskine/CTACK (CCL27) and MEC (CCL28). The CXC chemokine family (CXCL1–16) includes GROα (CXCL1), GROβ (CXCL2), GROγ (CXCL3), platelet factor 4 (CXCL4), ENA78 (CXCL5), GCP-2 (CXCL6), NAP-2 (CXCL7), IL-8 (CXCL8), MIG (CXCL9), IP10 (CXCL10), I-TAC (CXCL11), SDF-1 (CXCL12), BLC (CXCL13), BRAK (CXCL14), mouse lungkine (CXCL15) and SR-PSOX (CXCL16). The CX3C chemokine (CX3CL1) is also known as fractalkine (neurotactin in the mouse). Unlike other chemokines, this molecule is multimodular containing a chemokine domain, an elongated mucin-like stalk, a transmembrane domain and a cytoplasmic tail. Both plasma membrane-associated and shed forms have been identified. The C chemokine (XCL1) is also known as lymphotactin. The non-chemokine family includes the cytokine domain of tyrosyl-tRNA synthetase, HBD2, HIV gp120 and HIV Tat.

Abbreviations: BLC, B-lymphocyte chemokine; ELC, Epstein-Barr virus-induced receptor ligand chemokine; ENA-78, epithelial cell-derived neutrophil-activating factor-78 amino acids; GCP-2, granulocyte chemoattractant protein 2; HBD2, human β defensin 2; HCC, hemofiltrate CC chemokine; IL-8, interleukin 8; IP-10, γ-interferon-inducible protein 10; I-TAC, interferon-inducible T-cell α chemoattractant; LARC, liver and activation-related chemokine (CCL20); MCP, monocyte chemoattractant protein; MDC, macrophage-derived chemokine; MEC, mucosa expressed chemokine; MIG, monokine-induced by γ-interferon; MIP, macrophage inflammatory protein; MPIF-1, myeloid progenitor inhibitory factor 1; NAP-2, neutrophil-activating peptide 2; RANTES, regulated on activation normal T cell expressed and secreted; SDF, stromal cell-derived factor; SEAP, secreted alkaline phosphatase; SLC, secondary lymphoid tissue chemokine; TARC, T-cell and activation-related chemokine; TECK, thymus-expressed chemokine

Further Reading

Ali S, O'Boyle G, Mellor P, Kirby JA (2007). An apparent paradox: chemokine receptor agonists can be used for anti-inflammatory therapy. Mol Immunol44: 1477–1482.

Allen SJ, Crown SE, Handel TM (2007). Chemokine: receptor structure, interactions, and antagonism. Annu Rev Immunol25: 787–820.

Bizzarri C, Beccari AR, Bertini R, Cavicchia MR, Giorgini S, Allegretti M (2006). ELR + CXC chemokines and their receptors (CXC chemokine receptor 1 and CXC chemokine receptor 2) as new therapeutic targets. Pharmacol Ther112: 139–149.

Charo IF, Ransohoff RM (2006). The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med354: 610–621.

Donnelly LE, Barnes PJ (2006). Chemokine receptors as therapeutic targets in chronic obstructive pulmonary disease. Trends Pharmacol Sci27: 546–553.

Hansell CA, Simpson CV, Nibbs RJ (2006). Chemokine sequestration by atypical chemokine receptors. Biochem Soc Trans34: 1009–1013.

Kakinuma T, Hwang ST (2006). Chemokines, chemokine receptors, and cancer metastasis. J Leukoc Biol79: 639–651.

Lim JK, Glass WG, McDermott DH, Murphy PM (2006). CCR5: no longer a “good for nothing” gene-chemokine control of West Nile virus infection. Trends Immunol27: 308–312.

Lusso P (2006). HIV and the chemokine system: 10 years later. EMBO J25: 447–456.

Mantovani A, Bonecchi R, Locati M (2006). Tuning inflammation and immunity by chemokine sequestration: decoys and more. Nat Rev Immunol6: 907–918.

Murphy PM, Baggiolini M, Charo IF, Hebert CA, Horuk R, Matsushima K et al. (2000). International Union of Pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacol Rev52: 145–176.

Murphy PM (2002). International Union of Pharmacology. XXX. Update on chemokine receptor nomenclature. Pharmacol Rev54: 227–229.

Panina P, Mariani M, D'Ambrosio D (2006). Chemokine receptors in chronic obstructive pulmonary disease (COPD). Curr Drug Targets7: 669–674.

Proudfoot AE (2006). The biological relevance of chemokine-proteoglycan interactions. Biochem Soc Trans34: 422–426.

Ruffini PA, Morandi P, Cabioglu N, Altundag K, Cristofanilli M (2007). Manipulating the chemokine-chemokine receptor network to treat cancer. Cancer109: 2392–2404.

Tsibris AM, Kuritzkes DR (2007). Chemokine antagonists as therapeutics: focus on HIV-1. Annu Rev Med58: 445–459.

Viola A, Contento RL, Molon B (2006). T cells and their partners: The chemokine dating agency. Trends Immunol27: 421–427.

Weber C, Koenen RR (2006). Fine-tuning leukocyte responses: towards a chemokine ‘interactome’. Trends Immunol27: 268–273.

Wells TN, Power CA, Shaw JP, Proudfoot AE (2006). Chemokine blockers-therapeutics in the making? Trends Pharmacol Sci27: 41–47.

Zlotnik A, Yoshie O (2000). Chemokines: a new classification system and their role in immunity. Immunity12: 121–127.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Cholecystokinin

Overview: Cholecystokinin receptors (nomenclature recommended by the NC-IUPHAR Subcommittee on CCK receptors, Noble et al., 1999) are activated by the endogenous peptides cholecystokinin (CCK)-4, CCK-8, CCK-33 and gastrin. There is evidence for species homologues of CCK2 receptors distinguished by the relative affinities of the two stereoisomers of devazepide, R-L365260 and S-L365260, or by the differences in affinity of the agonist BC264 (Durieux et al., 1992).

NomenclatureCCK1CCK2
Other namesCCKACCKB, CCKB/gastrin
Ensembl IDENSG00000163394ENSG00000110148
Principal transductionGq/11/GsGs
Rank order of potencyCCK-8 > > gastrin, des-CCK-8 > CCK-4CCK-8 ≥ gastrin, des-CCK-8, CCK-4
Selective agonistsA71623, JMV180, GW5823Desulfated CCK-8, gastrin, CCK-4, BC264, RB400
Selective antagonistsDevazepide (9.8), T0632 (9.6), SR27897 (9.2), IQM95333 (9.2), PD140548 (7.9–8.6), lorglumide (7.2)YM022 (10.2), L740093 (10.0), GV150013 (9.3), RP73870 (9.3), L365260 (7.5–8.7), LY262691 (7.5)
Probes[3 H]-Devazepide (0.2 nM)[3 H]-Propionyl-BC264 (0.15 nM), [3 H]-PD140376 (0.2 nM), [3 H]-L365260 (2 nM), [3 H]- or [125I]-gastrin (1 nM), [125I]-PD142308 (0.25 nM)

A mitogenic gastrin receptor, which can be radiolabelled with [125I]-gastrin-(1–17) and which appears to couple to the Gs family of G proteins, has been described in human colon cancer cells (Bold et al., 1994) and other cell lines (e.g. pancreatic AR42J and Swiss 3T3 fibroblasts, Seva et al., 1994; Singh et al., 1995).

Abbreviations: A71623, Boc-Trp-Lys(O-toluylaminocarbonyl)-Asp-(NMe)Phe-NH2; BC264, Tyr(SO3H)-gNle-mGly-Trp-(NMe)Nle-Asp-Phe-NH2; GV150013, (+)-N-(1-[1-adamantane-1-methyl]-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl)-N'-phenylurea; ZGW5823, 2-[3-(1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(methyoxyphenyl)acetamide; IQM95333, (4αS,5R)-2-benzyl-5[N-(tert-butoxycarbonyl)-L-Trp]amino-1,3-dioxoperhydropyrido[1,2-c]pyrimidine; JMV180, Boc-Tyr(SO3H)Ahx-Gly-Trp-Ahx-Asp2phenylethyl ester; L365260, 3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea; L740093,N-([3R]-5-[3-azabicyclo{3.2.2}nonan-3-yl]-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl)urea; LY262691,trans-N-(4-bromophenyl)-3-oxo-4,5-diphenyl-1-pyrrazolidinecarboxamide(3.3.1.13,7); PD140376, L-3-([4-aminophenyl]methyl)-N-(a-methyl-N-[{tricyclo(3.3.1.1D-Trp)-b-Ala; PD140548, N-(a-methyl-N-[{tricyclo(3.3.1.1L-Trp)-D-3-(phenylmethyl)-b-Ala; PD142308, iodinated PD140548; RB400, HOOC-CH2-CO-Trp-NMe(Nle)-Asp-Phe-NH2; RP73870, ({[(RS); SR27897, 1-([2-{4-(2-chlorophenyl)thiazole-2-yl}amino-carbonyl]indolyl)acetic acid; T0632, sodium (S)-3-(1-[2-fluorophenyl]-2,3-dihydro-3-[{3-isoquinolinyl}-carbonyl]amino-6-methoxy-2-oxo-1H-indole)propanoate; YM022, (R)-1-(2,3-dihydro-1-[2′-methylphenacyl]-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-3-(3-methylphenyl)urea

Further Reading

De Tullio P, Delarge J, Pirotte B (2000). Therapeutic and chemical developments of cholecystokinin receptor ligands. Expert Opin Investig Drugs9: 129–146.

Dufresne M, Seva C, Fourmy D (2006). Cholecystokinin and gastrin receptors. Physiol Rev86: 805–847.

Herranz R (2003). Cholecystokinin antagonists: pharmacological and therapeutic potential. Med Res Rev23: 559–605.

Inui A (2003). Neuropeptide gene polymorphisms and human behavioural disorders. Nat Rev Drug Discov2: 986–998.

Kopin AS, McBride EW, Schaffer K, Beinboen M (2000). CCK receptor polymorphisms: an illustration of emerging themes in pharmacogenomics. Trends Pharmacol Sci21: 346–353.

Moran TH (2000). Cholecystokinin and satiety: current perspectives. Nutrition16: 858–865.

Noble F, Roques BP (1999). CCKB receptor: chemistry, molecular biology, biochemistry and pharmacology. Prog Neurobiol56: 1–31.

Noble F, Wank SA, Crawley JN, Bradwejn J, Seroogy KB, Hamon M, Roques BP (1999). International Union of Pharmacology. XXI. Structure, distribution, and functions of cholecystokinin receptors. Pharmacol Rev51: 745–781.

Peter SA, D'Amato M, Beglinger C (2006). CCKI antagonists: are they ready for clinical use? Dig Dis24: 70–82.

Rozengurt E, Walsh J (2001). Gastrin, CCK, signaling, and cancer. Annu Rev Physiol63: 49–76.

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Bold RJ et al. (1994). Biochem Biophys Res Commun202: 1222–1226.

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Seva C et al. (1994). Science265: 410–412.

Singh P et al. (1995). J Biol Chem270: 8429–8438.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Corticotropin-releasing factor

Overview: Corticotropin-releasing factor (CRF, nomenclature as recommended by the NC-IUPHAR on Corticotropin-releasing Factor Receptors, see Hauger et al., 2003) receptors are activated by the endogenous peptides CRF (also known as corticotropin-releasing hormone [CRH], a 41 amino-acid peptide, ENSG00000147571), urocortin 1 (a 40 amino-acid peptide, ENSG00000163794), urocortin 2 (a 38 amino-acid peptide, ENSG00000145040) and urocortin 3 (a 38 amino-acid peptide, ENSG00000178473). CRF1 and CRF2 receptors are activated non-selectively by CRF and urocortin 1. Binding to CRF receptors can be conducted using [125I]-Tyr0-CRF or [125I]-Tyr0-sauvagine with Kd values of 0.1-0.4 nM. CRF1 and CRF2 receptors are non-selectively antagonized by α-helical CRF-(9-41), D-Phe-CRF-(12-41) and astressin.

NomenclatureCRF1CRF2
Other namesCRF-RA, PC-CRFCRF-RB, HM-CRF
Ensembl IDENSG00000120088ENSG00000106113
Principal transductionGsGs
Selective agonistsUrocortin 2 (Reyes et al., 2001), urocortin 3 (Lewis et al., 2001)
Selective antagonistsCP154526 (8.3–9.0, Lundkvist et al., 1996), NBI27914 (8.3–9.0, Chen et al., 1996), antalarmin (8.3–9.0, Webster et al., 1996), CRA1000 (8.3–9.0, Chaki et al., 1999), DMP696 (8.3–9.0, He et al., 2000), R121919 (8.3–9.0, Zobel et al., 2000), SRA125543A (8.7–9.0, Gully et al., 2002)K41498 (9.2, Lawrence et al., 2002), K31440 (8.7–8.8, Ruhmann et al., 2002), antisauvagine-30 (Ruhmann et al., 1998)

A CRF binding protein has been identified (CRF-BP, ENSG00000145708) to which both CRF and urocortin 1 bind with high affinities, which has been suggested to bind and inactivate circulating CRF (Perkins et al., 1995).

Abbreviations: antalarmin,N-butyl-N-ethyl-(2,5,6-trimethyl)-7-[2,4,6-trimethylphenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl-amine; astressin,cyc30–33[D-Phe12,Nle21,38,Glu30,Lys33]CRF-(12-41); CP154526, butyl-ethyl-(2,5-dimethyl-7-[2,4,6-trimethylphenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amine; CRA1000, 2-(N-[2-methylthio-4-isopropylphenyl]-N-ethyl-amino-4-[4-{3-fluorophenyl}-1,2,3,6-tetrahydropyridin-1-yl]-6-methyl-pyrimidine); DMP696, 4-(1,3-dimethoxyprop-2-ylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)pyrazolo[1,5-α]-1,3,5-triazine; D-Phe-CRF-(12-41), D-Phe12,Nle21,38,αMeLeu37-CRF; K31440, Ac-(D-Tyr11,His12 Nle17)sauvagine-(11-40); K41498, [D-Phe11,His12,Nle17]sauvagine-(11-40); NBI27914, 2-methyl-4-(N-propyl-N-cyclopropanemethylamino)-5-chloro-6-(2,4,6-trichloroanilino)pyrimidine; R121919, 3-[6-(dimethylamino)-4-methyl-3-pyridinyl]-2,5-dimethyl-N,N-dipropylpyrazolo[1,5-a]pyrimidin-7-amine; SRA125543A, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride

Further Reading

Arzt E, Holsboer F (2006). CRF signaling: molecular specificity for drug targeting in the CNS. Trends Pharmacol Sci27: 531–538.

Bale TL, Vale WW (2004). CRF and CRF receptors: role in stress responsivity and other behaviors. Annu Rev Pharmacol Toxicol44: 525–557.

Fekete EM, Zorrilla EP (2007). Physiology, pharmacology, and therapeutic relevance of urocortins in mammals: ancient CRF paralogs. Front Neuroendocrinol28: 1–27.

Gilligan PJ, Li YW (2004). Corticotropin-releasing factor antagonists: recent advances and exciting prospects for the treatment of human diseases. Curr Opin Drug Discov Devel7: 487–497.

Gravanis A, Margioris AN (2005). The corticotropin-releasing factor (CRF) family of neuropeptides in inflammation: potential therapeutic applications. Curr Med Chem12: 1503–1512.

Grigoriadis DE (2005). The corticotropin-releasing factor receptor: a novel target for the treatment of depression and anxiety-related disorders. Expert Opin Ther Targets9: 651–684.

Hauger RL, Grigoriadis DE, Dallman MF, Plotsky PM, Vale WW, Dautzenberg FM (2003). International Union of Pharmacology. XXXVI. Current Status of the Nomenclature for Receptors for Corticotropin-Releasing Factor and Their Ligands. Pharmacol Rev55: 21–26.

Hillhouse EW, Grammatopoulos DK (2006). The molecular mechanisms underlying the regulation of the biological activity of corticotropin-releasing hormone receptors: implications for physiology and pathophysiology. Endocr Rev27: 260–286.

Nielsen DM (2006). Corticotropin-releasing factor type-1 receptor antagonists: the next class of antidepressants? Life Sci78: 909–919.

Orozco-Cabal L, Pollandt S, Liu J, Shinnick-Gallagher P, Gallagher JP (2006). Regulation of synaptic transmission by CRF receptors. Rev Neurosci17: 279–307.

Tache Y, Bonaz B (2007). Corticotropin-releasing factor receptors and stress-related alterations of gut motor function. J Clin Invest117: 33–40.

Theoharides TC, Donelan JM, Papadopoulou N, Cao J, Kempuraj D, Conti P (2004). Mast cells as targets of corticotropin-releasing factor and related peptides. Trends Pharmacol Sci25: 563–568.

Westphal NJ, Seasholtz AF (2006). CRH-BP: the regulation and function of a phylogenetically conserved binding protein. Front Biosci11: 1878–1891.

Ziegler CG, Krug AW, Zouboulis CC, Bornstein SR (2007). Corticotropin releasing hormone and its function in the skin. Horm Metab Res39: 106–109.

References

Chaki S et al. (1999). Eur J Pharmacol371: 205–211.

Chen C et al. (1996). J Med Chem39: 4358–4360.

Gully D et al. (2002). J Pharmacol Exp Ther301: 322–332.

He L et al. (2000). J Med Chem43: 449–456.

Lawrence AJ et al. (2002). Br J Pharmacol136: 896–904.

Lewis K et al. (2001). Proc Natl Acad Sci USA98: 7570–7575.

Lundkvist J et al. (1996). Eur J Pharmacol309: 195–200.

Perkins AV et al. (1995). J Endocrinol146: 395–401.

Reyes TM et al. (2001). Proc Natl Acad Sci USA98: 2843–2848.

Ruhmann A et al. (1998). Proc Natl Acad Sci USA95: 15264–15269.

Ruhmann A et al. (2002). Peptides23: 453–460.

Webster EL et al. (1996). Endocrinology137: 5747–5750.

Zobel AW et al. (2000). J Psychiatr Res34: 171–181.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Dopamine

Overview: Dopamine receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Dopamine Receptors, see Schwartz et al., 1998) are commonly divided into D1-like (D1 and D5) and D2-like (D2, D3 and D4) families, where the endogenous agonist is dopamine. Quinpirole is an agonist with selectivity for D2-like receptors.

NomenclatureD1D2D3D4D5
Other namesD1, D1AD2D3D4D5, D1B
Ensembl IDENSG00000184845ENSG00000149295ENSG00000151577ENSG00000069696ENG00000169676
Principal transductionGs,GolfGi/oGi/oGi/oGs
Selective agonistsR(+)SKF81297, R(+)SKF38393PD128907PD168077, A412997 (Moreland et al., 2005)
Selective antagonistsSCH23390, SKF83566, SCH39166Raclopride, domperidoneS33084 (9.6, Millan et al., 2000), nafadotride (9.5), (+)S14297 (8.7, Millan et al., 1994), SB277011 (7.5, Reavill et al., 2000)L745870 (9.3), U101958 (8.9, Schlachter et al., 1997), L741742 (8.5)
Probes[3H]-SCH23390 (0.2 nM), [125I]-SCH23982 (0.7 nM)[3H]-Raclopride, [[3H]-spiperone[3H]-7-OH-DPAT, [3H]-PD128907, [3H]-spiperone[3H]-NGD941 (5 nm, Primus et al., 1997), [125I]-L750667 (1 nM, Patel et al., 1996), [3H]-spiperone[125I]-SCH23982 (0.8 nM) [3H]-SCH23390 (0.5 nM)

The selectivity of many of these agents is less than two orders of magnitude. [3H]-Raclopride exhibits similar high affinity for D2 and D3 receptors (low affinity for D4), but has been used to label D2 receptors in the presence of a D3-selective antagonist. [3H]-7-OH-DPAT has similar affinity for D2 and D3 receptors, but labels only D3 receptors in the absence of divalent cations. The pharmacological profile of the D5 receptor is similar to, yet distinct from, that of the D1 receptor. The splice variants of the D2 receptor are commonly termed D2S and D2L (short and long). The DRD4 gene is highly polymorphic in humans, with allelic variations of the protein from amino acid 387-515.

Abbreviations: L741742, 5-(4-chlorophenyl)-4-methyl-3-(1-[2-phenethyl]piperidin-4-yl)isoxazole; L745870, 3-[{4-(4-chlorophenyl)piperazin-1-yl}methyl)-1H-pyrrolo[2,3-b]pyridine; L750667, iodinated L745870; NGD941, 2-phenyl-4(S)-(4-[2-pyrimidinyl]-[piperazin-1-yl]-methyl)-imidazole dimaleate; (+)7-OH-DPAT, (+)-7-hydroxy-2-aminopropylaminotetralin; PD128907,R-(+)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazine-9-ol; PD168077,N-methyl-4-(2-cyanophenyl)piperazinyl-3-methylbenzamide; (+)S14297, (+)-7-(N,N-dipropylamino)-5,6,7,8-tetrahydronaphtho(2,3b)dihydro-2,3-furane; S33084, (3aR,9bS)-N[4-(8-cyano-1,3a,4,9b-tetrahydro-3H-benzopyr-ano[3,4-c]pyrrole-2-yl)-butyl] (4-phenyl)benzamide; SB277011,trans-N-(4-[2-{6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl}ethyl]cyclohexyl)-4-quinolininecarboxamide; SCH23390, 7-chloro-8-hydroxy-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; SCH23982, 8-iodo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine; SCH39166, (-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-ethyl-5H-benzo[d]-naphtho-(2,b)azepine; R(+)SKF38393,R(+)-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; R(+)SKF81297,R(+)-6-chloro7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-benzazepine; SKF83566, (-)-7-bromo-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-3-benzaze-pine; U101958, 3-isopropoxy-N-methyl-N-(1-[phenylmethyl]-4-piperidinyl)-2-pyridinylamine

Further Reading

Agnati LF, Ferre S, Burioni R, Woods A, Genedani S, Franco R et al. (2005). Existence and theoretical aspects of homomeric and heteromeric dopamine receptor complexes and their relevance for neurological diseases. Neuromolecular Med 7: 61–78.

Beaulieu JM, Gainetdinov RR, Caron MG (2007). The Akt-GSK-3 signaling cascade in the actions of dopamine. Trends Pharmacol Sci28: 166–172.

Bjorklund A, Dunnett SB (2007a). Dopamine neuron systems in the brain: an update. Trends Neurosci30: 194–202.

Bjorklund A, Dunnett SB (2007b). Fifty years of dopamine research. Trends Neurosci30: 185–187.

Bonci A, Hopf FW (2005). The dopamine D2 receptor: new surprises from an old friend. Neuron47: 335–338.

Horowski R (2007). A history of dopamine agonists. From the physiology and pharmacology of dopamine to therapies for prolactinomas and Parkinson's disease - a subjective view. J Neural Transm114: 127–134.

Iversen SD, Iversen LL (2007). Dopamine: 50 years in perspective. Trends Neurosci30: 188–193.

Joyce JN, Millan MJ (2007). Dopamine D3 receptor agonists for protection and repair in Parkinson's disease. Curr Opin Pharmacol7: 100–105.

Marsden CA (2006). Dopamine: the rewarding years. Br J Pharmacol147: S136–S144.

Redgrave P, Gurney K (2006). The short-latency dopamine signal: a role in discovering novel actions? Nat Rev Neurosci7: 967–975.

Schwartz J-C et al. (1998). Dopamine receptors. In: Girdlestone D (ed). The IUPHAR Compendium of Receptor Characterization and Classification. IUPHAR Media: London, pp 141–151.

Strange PG (2005). Oligomers of D2 dopamine receptors: evidence from ligand binding. J Mol Neurosci26: 155–160.

References

Millan MJ et al. (1994). Eur J Pharmacol260: R3–R5.

Millan MJ et al. (2000). J Pharmacol Exp Ther293: 1048–1062.

Moreland RB et al. (2005). Pharmacol Biochem Behav82: 140–147.

Patel S et al. (1996). Mol Pharmacol50: 1658–1664.

Primus RJ et al. (1997). J Pharmacol Exp Ther282: 1020–1027.

Reavill C et al. (2000). J Pharmacol Exp Ther294: 1154–1165.

Schlachter SK et al. (1997). Eur J Pharmacol322: 283–286.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Endothelin

Overview: Endothelin receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Endothelin Receptors, Davenport, 2002) are activated by the endogenous 21 amino-acid peptides endothelin-1 (ET-1, ENSG00000078401), ET-2 (ENSG00000127129) and ET-3 (ENSG00000124205). Non-selective peptide (e.g. TAK044, pA2 8.4) and non-peptide (e.g. bosentan, pA2 6.0-7.2; SB209670, pA2 9.4) antagonists can block both ETA and ETB receptors. Splice variants of the ETA receptor have been identified in rat pituitary cells; one of these, ETAR-C13, appeared to show loss of function with comparable plasma membrane expression (Hatae et al., 2007).

NomenclatureETAETB
Ensemble IDENSG00000151617ENSG00000136160
Principal transductionGq/11, GsGq/11, Gi/o
Potency orderET-1, ET-2>ET-3 (Maguire and Davenport, 1995)ET-1, ET-2, ET-3
Selective agonists[Ala1,3,11,15]ET-1 (Molenaar et al., 1992), sarafotoxin S6c (Russell and Davenport, 1996), IRL1620 (Watakabe et al., 1992), BQ3020 (Russell and Davenport, 1996)
Selective antagonistsA127722 (9.2-10.5, Opgenorth et al., 1996), LU135252 (8.9, Riechers et al., 1996), SB234551 (8.7-9.0, Ohlstein et al., 1998), PD156707 (8.2-8.5, Maguire et al., 1997), FR139317 (7.3-7.9, Maguire and Davenport, 1995), BQ123 (6.9-7.4, Maguire and Davenport, 1995)BQ788 (8.4, Russell and Davenport, 1996), A192621 (8.1, von Geldern et al., 1999), IRL2500 (7.2, Russell and Davenport, 1996), Ro468443 (7.1, Breu et al., 1996)
Probes[3H]-S0139 (0.6 nM), [3H]-BQ123 (3.2 nM, Ihara et al., 1995), [125I]-PD164333 (0.2 nM, Davenport et al., 1998), [125I]-PD151242 (0.5 nM, Davenport et al., 1994)[125I]-IRL1620 (20 pM, Watakabe et al., 1992), [125I]-BQ3020 (0.1 nM, Molenaar et al., 1992), [125I]-[Ala1,3,11,15]ET-1 (0.2 nM, Molenaar et al., 1992)

Subtypes of the ETB receptor have been proposed, although gene disruption studies in mice suggest that the heterogeneity results from a single gene product (Mizuguchi et al., 1997).

Abbreviations: A127722,trans-trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-([N,N-dibutylamino]carbonylmethyl)pyrrolidine-3-car-boxylate; A192621, (2R,3R,4S)-2-(4-propoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-[2,6-diethylphenyl]acetamido)pyrrolidine-3-carboxylic acid; BQ123,cyc(DTrp-DAsp-Pro-D-Val-Leu); BQ3020,N-acetyl-Leu-Met-Asp-Lys-Glu-Ala-Val-Tyr-Phe-Ala-His-Leu-Asp-Ile-Ile-Trp; BQ788,N-cis-2,6-dimethylpiperidinocarbonyl-L-γ-methylleucyl-D-1-methoxycarboyl-D-norleucine; FR139317, (R)2-([R-2-{(S)-2-([1-{hexahydro-1H-azepinyl}car-bonyl]amino)methyl}pentanoyl]amino-3-(3-[methyl-1H-indodyl])propionylamino-3-(2-pyridyl))propionate; IRL1620, Suc[Glu9,Ala11,15]ET-110-21; IRL2500,N-(3,5-dimethylbenzoyl)-N-methyl-(D)-(4-phenylphenyl)-Ala-Trp; LU135252, (+)-(S)-2-(4,6-dimethoxypyrimidin-2-yloxy)-3-meth-oxy-3,3-propionic acid; PD151242, (N-[{hexahydro-1-azepinyl}carbonyl])Leu(1-Me)-DTrp-DTyr; PD156707, 2-benzo[1,3]dioxol-5-yl-4-(4-meth-oxyphenyl)-4-oxo-3-(3,4,5-trimethoxybenzyl)-but-2-enoate; PD164333, 2-benzo[1,3]dioxol-5-yl-4-(3-[2-(4-hydroxy-phenyl)-ethylcarbamoyl]-propoxy)-4,5-dimethoxy-phenyl-3-(4-methoxy-benzoyl)-but-2-enoate; RES7011,cyc(Gly-Asn-Trp-His-Gly-Thr-Ala-Pro-Asp)-Trp-Phe-Phe-Asn-Tyr-Tyr-Trp; Ro468443, (R)-4-tert-butyl-N-(6-[2,3-dihydroxypropoxy]-5-[2-methoxyphenoxy]-2-[4-methoxyphenyl]-pyrimidin-4-yl)-benzene-sulfonamide; S0139, 27-O-3-(2-[3-carboxyacryloylamino]-5-hydroxyphenyl)-acryloyloxymyricone, sodium salt; SB209670, (+)-1S,2R,S-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-prop-1-yloxyindane-2-carboxylate; SB234551, (E)-α-([1-butyl-5-{2-([2-carboxyphenyl]methoxy)-4-methoxyphenyl}-1H-pyrazol-4-yl]methylene)-6-methoxy-1,3-benzodioxole-5-propanoic acid; TAK044,cyc(D-Asp-Asp(Php)-Asp-D-Thg-Leu-D-Trp)-4-oxobut-2-enoate

Further Reading

Davenport AP (2002). International union of pharmacology. XXIX. Update on endothelin receptor nomenclature. Pharmacol Rev54: 219–226.

Davenport AP, Maguire JJ (2006). Endothelin. Handb Exp Pharmacol176: 295—329.

Galie N, Manes A, Branzi A (2004). The endothelin system in pulmonary arterial hypertension. Cardiovasc Res61: 227–237.

Iqbal J, Sanghia R, Das SK (2005). Endothelin receptor antagonists: an overview of their synthesis and structure-activity relationship. Mini Rev Med Chem5: 381–408.

Masaki T (2004). Historical review: endothelin. Trends Pharmacol Sci25: 219–224.

Motte S, McEntee K, Naeije R (2006). Endothelin receptor antagonists. Pharmacol Ther110: 386–414.

Rashid AJ, O'Dowd BF, George SR (2004). Minireview: diversity and complexity of signaling through peptidergic G protein-coupled receptors. Endocrinology145: 2645–2652.

Schinelli S (2006). Pharmacology and physiopathology of the brain endothelin system: an overview. Curr Med Chem13: 627–638.

Schneider MP, Boesen EI, Pollock DM (2007). Contrasting actions of endothelin ETA and ETB receptors in cardiovascular disease. Annu Rev Pharmacol Toxicol47: 731–759.

References

Breu V et al. (1996). FEBS Lett383: 37–41.

Davenport AP et al. (1994). Br J Pharmacol111: 4–6.

Davenport AP et al. (1998). Br J Pharmacol123: 223–230.

Hatae N et al. (2007). Mol Endocrinol21: 1192–1204.

Ihara M et al. (1995). Eur J Pharmacol274: 1–6.

Maguire JJ et al. (1997). J Pharmacol Exp Ther280: 1102–1108.

Maguire JJ, Davenport AP (1995). Br J Pharmacol115: 191–197.

Mizuguchi T et al. (1997). Br J Pharmacol120: 1427–1430.

Molenaar P et al. (1992). Br J Pharmacol107: 637–639.

Ohlstein EH et al. (1998). J Pharmacol Exp Ther286: 650–656.

Opgenorth TJ et al. (1996). J Pharmacol Exp Ther276: 473–481.

Riechers H et al. (1996). J Med Chem39: 2123–2128.

Russell FD, Davenport AP (1996). Br J Pharmacol119: 631–636.

von Geldern TW et al. (1999). J Med Chem42: 3668–3678.

Watakabe T et al. (1992). Biochem Biophys Res Commun185: 867–873.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Free fatty acid

Overview: Free fatty acid receptors (FFA, provisional nomenclature) are activated by free fatty acids, such that long chain saturated and unsaturated fatty acids (C16:0, C18:0, C18:1, C18:2, C18:3, n-6, C20:4, C20:5, n-3, C22:6, n-3, Briscoe et al., 2003; Itoh et al., 2003; Kotarsky et al., 2003) activate FFA1 receptors, while short chain fatty acids (C4, C3 & C2) activate FFA2 (Brown et al., 2003; Le Poul et al., 2003; Nilsson et al., 2003) and FFA3 (Brown et al., 2003; Le Poul et al., 2003) receptors. In addition, the thiazolidinedione PPARγ agonists rosiglitazone and troglitazone have been suggested to activate FFA1 (Kotarsky et al., 2003; Stoddart et al., 2007).

NomenclatureFFA1FFA2FFA3
Other namesGPR40 (Sawzdargo et al., 1997)GPR43 (Sawzdargo et al., 1997)GPR41 (Sawzdargo et al., 1997). LSSIG (Senga et al., 2003)
Ensembl IDENSG00000126266ENSG00000126262ENSG00000185897
Principal transductionGq/11 (Briscoe et al., 2003; Itoh et al., 2003; Kotarsky et al., 2003)Gq/11, Gi/o (Brown et al., 2003; Le Poul et al., 2003; Nilsson et al., 2003)Gq/11, Gi/o (Brown et al., 2003; Le Poul et al., 2003)
Selective agonistsLinoleic acid (Briscoe et al., 2003; Itoh et al. 2003), GW9508 (pEC50 7.3; Briscoe et al., 2006; Sum et al., 2007)
Selective antagonistsGW1100 (Briscoe et al., 2006; Stoddart et al., 2007)

GW1100 is also an oxytocin receptor antagonist (Briscoe et al., 2006).

GPR120 (ENSG00000186188) is an additional target for unsaturated long chain free fatty acids (Hirasawa et al., 2005; Katsuma et al., 2005; Gotoh et al., 2007) and GW9508 (pEC50 5.7; Briscoe et al., 2006). GPR42 (ENSG00000126251) is a further member of the family (ENSF00000003273) with as yet undefined characteristics (Brown et al., 2003).

Abbreviations: C16:0, palmitic acid; C18:0, stearic acid; C18:1, oleic acid; C18:2, linoleic acid; C18:3, n-6, γ-linolenic acid; C2, acetic acid; C20:4, arachidonic acid; C20:5, n-3, 5z,8z,11z,14z,17z-eicosapentaenoic acid, EPA; C22:6, n-3, 4z,7z,10z,13z,16z,19z-docosahexaenoic acid, DHA; C3, propionic acid; C4, butyric acid; GW1100, ethyl 4-(5-[{2-(ethyloxy)-5-pyrimidinyl}methyl]-2-[{(4-fluorophenyl)methyl]thio}-4-oxo-1[4H]-pyrimidinyl)benzoate; GW9508, 3-(4-[{(3-[phenyloxy]phenyl)methyl}amino]phenyl)propanoic acid

Further Reading

Brown AJ, Jupe S, Briscoe CP (2005). A family of fatty acid binding receptors. DNA Cell Biol24: 54–61.

Milligan G, Stoddart LA, Brown AJ (2006). G protein-coupled receptors for free fatty acids. Cell Signal18: 1360–1365.

Rayasam GV, Tulasi VK, Davis JA, Bansal VS (2007). Fatty acid receptors as new therapeutic targets for diabetes. Expert Opin Ther Targets11: 661–671.

References

Briscoe CP et al. (2003). J Biol Chem278: 11303–11311.

Briscoe CP et al. (2006). Br J Pharmacol148: 619–628.

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Gotoh C et al. (2007). Biochem Biophys Res Commun354: 591–597.

Hirasawa A et al. (2005). Nat Med11: 90–94.

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Kotarsky K et al. (2003). Pharmacol Toxicol93: 249–258.

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Nilsson NE et al. (2003). Biochem Biophys Res Commun303: 1047–1052.

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Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Frizzled

Overview: Receptors of the Frizzled class (FZD, provisional nomenclature, see Foord et al., 2005), which also includes Smoothened (Smo, ENSG00000128602), are 7TM receptors originally identified in Drosophila (Chan et al., 1992), which are highly conserved across species. FZD are activated by WNTs, which are palmitoylated, cysteine-rich glycoprotein hormones with fundamental functions in ontogeny and tissue homeostatis. FZD signalling was initially divided into two pathways, being either dependent on the accumulation of the transcription factor β-catenin (ENSG00000168036) or being β-catenin-independent (often referred to as canonical vs non-canonical WNT/FZD signaling, respectively). WNT stimulation of FZDs can, in cooperation with the low density lipoprotein receptors (LRP 5, ENSG00000162337 and LRP6, ENSG00000070018), lead to the inhibition of a constitutively active destruction complex, which results in the accumulation of β-catenin. β-Catenin, in turn, modifies gene transcription in concert with TCF/LEF transcription factors. β-Catenin-independent FZD signaling is far more complex with regard to the diversity of the activated pathways. WNT/FZD signalling can lead to the elevation of intracellular calcium (Slusarksi et al., 1997) and activation of cGMP-specific PDE6 (Ahumada et al., 2002), which has been implicated to be mediated through heterotrimeric G-proteins. FZD signalling can also occur through Dishevelled phosphoproteins (ENSF00000001536) to RAC-1 and JNK, as well as Rho and ROCK kinases. The pattern of cell signalling is complicated by the presence of additional ligands which can enhance (Norrin or R-spondin) or inhibit FZD function (secreted Frizzled-related proteins [sFRP], Wnt inhibitory factor [WIF], SOST or Dickkopf), as well as modulatory proteins with positive (Ryk, ENSG00000163785; ROR1, ENSG00000185483 and ROR2, ENSG00000169071) and negative (Kremen) regulatory features, which may also function as independent signalling proteins.

NomenclatureFZD1FZD2FZD3FZD4FZD5
Other namesFrizzled-1Frizzled-2Frizzled-3Frizzled-4, CD344Frizzled-5
Ensembl IDENSG00000157240ENSG00000180340ENSG00000104290ENSG00000174804ENSG00000163251
NomenclatureFZD6FZD7FZD8FZD9FZD10
Other namesFrizzled-6Frizzled-7Frizzled-8Frizzled-9, CD349Frizzled-10, CD350
Ensembl IDENSG00000164930ENSG00000155760ENSG00000177283ENSG00000188763ENSG00000111432

There is limited knowledge about WNT/FZD specificity and which molecular entities determine the signalling outcome of a specific WNT/FZD pair. There is also a scarcity of information on basic pharmacological characteristics of FZDs, such as binding constants, ligand specificity or concentration-response relationships.

Ligands associated with FZD signalling:WNTs: WNT1 (ENSG00000125084), WNT2 (ENSG00000105989, also known as Int-1-related protein), WNT2B (ENSG00000134245, also known as WNT-13), WNT3 (ENSG00000108379), WNT3A (ENSG00000154342), WNT4 (ENSG00000162552), WNT5A (ENSG00000114251), WNT5B (ENSG00000111186), WNT6 (ENSG00000115596), WNT7A (ENSG00000154764), WNT7B (ENSG00000188064), WNT8A (ENSG00000061492), WNT8B (ENSG00000075290), WNT9A (ENSG00000143816, also known as WNT-14), WNT9B (ENSG00000158955, also known as WNT-15 or WNT-14b), WNT10A (ENSG00000135925), WNT10B (ENSG00000169884, also known as WNT-12), WNT11 (ENSG00000085741) and WNT16 (ENSG00000002745).

Proteins that interact with FZDs: Norrin (ENSG00000124479), R-spondin 1 (ENSG00000169218), R-spondin 2 (ENSG00000147655), R-spondin 3 (ENSG00000146374), R-spondin 4 (ENSG00000101282), sFRP 1 (ENSG00000104332), sFRP 2 (ENSG00000145423), sFRP 3 (ENSG00000162998), sFRP 4 (ENSG00000106483), sFRP 5 (ENSG00000120057),

Proteins that interact with WNTs or LRPs: Dickkopf 1 (ENSG00000104901), WIF 1 (ENSG00000156076), SOST (ENSG00000167941), Kremen 1 (ENSG00000183762) and Kremen 2 (ENSG00000131650)

Abbreviations: FZD, Frizzled; TCF/LEF, ternary complex factor/lymphoid enhancer binding factor

Further Reading

Cadigan KM, Liu YI (2006). Wnt signaling: complexity at the surface. J Cell Sci119: 395–402.

Chien AJ, Moon RT (2007). WNTS and WNT receptors as therapeutic tools and targets in human disease processes. Front Biosci12: 448–457.

Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP et al. (2005). International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol Rev57: 279–288.

Gordon MD, Nusse R (2006). Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors. J Biol Chem281: 22429–22433.

Kikuchi A, Yamamoto H, Kishida S (2007). Multiplicity of the interactions of Wnt proteins and their receptors. Cell Signal19: 659–671.

Luo J, Chen J, Deng ZL, Luo X, Song WX, Sharff KA et al. (2007). Wnt signaling and human diseases: what are the therapeutic implications? Lab Invest87: 97–103.

Malbon CC (2004). Frizzleds: new members of the superfamily of G-protein-coupled receptors. Front Biosci9: 1048–1058.

Malbon CC, Wang HY (2006). Dishevelled: a mobile scaffold catalyzing development. Curr Top Dev Biol72: 153–166.

Schulte G, Bryja V (2007). The Frizzled family of unconventional G protein-coupled receptors. Trends Pharmacol Sci28: 518–525.

Seifert JR, Mlodzik M (2007). Frizzled/PCP signalling: a conserved mechanism regulating cell polarity and directed motility. Nat Rev Genet8: 126–138.

Speese SD, Budnik V (2007). Wnts: up-and-coming at the synapse. Trends Neurosci30: 268–275.

Wang HY, Liu T, Malbon CC (2006). Structure-function analysis of Frizzleds. Cell Signal18: 934–941.

Wang HY, Malbon CC (2004). Wnt-frizzled signaling to G-protein-coupled effectors. Cell Mol Life Sci61: 69–75.

References

Ahumada A et al. (2002). Science298: 2006–2010.

Chan SD et al. (1992). J Biol Chem267: 25202–25207.

Slusarski DC et al. (1997). Nature390: 410–413.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

GABAB

Overview: Functional GABAB receptors (nomenclature agreed by NC-IUPHAR Subcommittee on GABAB receptors, Bowery et al., 2002; see also Pin et al., 2007) are formed from the heterodimerization of two similar 7TM subunits termed GABAB1 and GABAB2 (Bowery et al., 2002; Pin et al., 2004, 2007). The GABAB1 subunit, when expressed alone, binds both antagonists and agonists, but the affinity of the latter is generally 10-100-fold less than for the native receptor. The GABAB1 subunit when expressed alone is not transported to the cell membrane and is non-functional. Co-expression of GABAB1 and GABAB2 subunits allows transport of GABAB1 to the cell surface and generates a functional receptor that can couple to signal transduction pathways such as high-voltage-activated Ca2+ channels (Cav2.1, Cav2.2), or inwardly rectifying potassium channels (Kir3) (Bowery and Enna, 2000; Bowery et al., 2002; Bettler et al., 2004). The GABAB1 subunit harbours the GABA (orthosteric)-binding site within an extracellular domain (ECD) venus flytrap module (VTM), whereas the GABAB2 subunit mediates G-protein coupled signalling (Bowery et al., 2002, Pin et al., 2004). The two subunits interact allosterically in that GABAB2 increases the affinity of GABAB1 for agonists and reciprocally GABAB1 facilitates the coupling of GABAB2 to G-proteins (Pin et al., 2004; Kubo and Tateyama, 2005). GABAB1 and GABAB2 subunits assemble in a 1:1 stoichiometry by means of a coiled-coil interaction between α-helices within their carboxy-termini that masks an endoplasmic reticulum retention motif (RXRR) within the GABAB1 subunit but other domains of the proteins also contribute to their heteromerization (Bettler et al., 2004; Pin et al., 2004). Four isoforms of the human GABAB1 subunit have been cloned. The predominant GABAB1(a) and GABAB1(b) isoforms, which are most prevalent in neonatal and adult brain tissue respectively, differ in their ECD sequences as a result of the use of alternative transcription initiation sites. GABAB1(a)-containing heterodimers localise to distal axons and mediate inhibition of glutamate release in the CA3-CA1 terminals, and GABA release onto the layer 5 pyramidal neurons, whereas GABAB1(b)-containing receptors occur within dendritic spines and mediate slow postsynaptic inhibition (Vigot et al., 2006; Pérez-Garci et al., 2006). Isoforms generated by alternative splicing are GABAB1(c) that differs in the ECD, and GABAB1(e), which is a truncated protein that can heterodimerize with the GABAB2 subunit but does not constitute a functional receptor. Only the 1a and 1b variants are identified as components of native receptors (Bowery et al., 2002). Additional GABAB1 subunit isoforms have been described in rodents (reviewed by Bettler et al., 2004).

NomenclatureGABAB
Ensembl IDGABAB1 ENSG00000168760; GABAB2 ENSG00000136928
Principal transductionGi/o
Selective agonists3-APPA (CGP27492, 5 nM), 3-APMPA (CGP35024, 16 nM), (R)-(-)-baclofen (32 nM), CGP44532 (45 nM)
Selective antagonistsCGP62349 (2.0 nM), CGP55845 (6 nM), SCH50911 (3 μM), 2-hydroxy-s-(-)-saclofen (11 μM), CGP35348 (27 μM)
Probes (KD)[3H](R)-(-)-baclofen, [3H]CGP54626 (1.5 nM; Bittiger et al., 1992), [3H]CGP62349 (0.9 nM, Kier et al., 1999), [125I]CGP64213 (1 nM, Galvez et al., 2000), [125I]CGP71872 (Ki = 0.5 nM, Belley et al., 1999)

Potencies of agonists and antagonists listed in the table, quantified as IC50 values for the inhibition of [3H]CGP27492 binding to rat cerebral cortex membranes, are from Froestl and Mickel (1997) and Bowery et al. (2002). Radioligand KD values relate to binding to rat brain membranes. CGP71872 is a photoaffinity ligand for the GABAB1 subunit (Belley et al., 1999). In addition to the ligands listed in the table, Ca2+ binds to a site on the GABAB1 subunit to act as a positive allosteric modulator of GABA (Galvez et al., 2000). In cerebellar Purkinje neurones, the interaction of Ca2+ with the GABAB receptor enhances the activity of mGlu1, most probably via a direct association between the two receptors (Tabata et al., 2004). Synthetic positive allosteric modulators with little, or no, intrinsic activity include CGP7930 and GS39783 (reviewed by Bettler et al., 2004; Adams and Lawrence, 2007). Their site of action appears to be on the heptahelical domain of the GABAB2 subunit (Pin et al., 2004; Dupuis et al., 2006). Knock-out of the GABAB1 subunit in C57B mice causes the development of severe tonic-clonic convulsions that prove fatal within a month of birth, whereas GABAB1-/- BALB/c mice, although also displaying spontaneous epileptiform activity, are viable. The phenotype of the latter animals additionally includes hyperalgesia, hyperlocomotion (in a novel, but not familiar, environment), hyperdopaminergia, memory impairment and behaviours indicative of anxiety (Enna and Bowery, 2004; Vacher et al., 2006). A similar phenotype has been found for GABAB2-/- BALB/c mice (Gassmann et al., 2004).

Abbreviations: 3-APMPA (CGP35024), 3-amino-propyl-(P-methyl)-phosphinic acid; 3-APPA (CGP27492), 3-amino-propyl-phosphinic acid; CGP7930, 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol; CGP35348, p-(3-aminopropyl)-P-diethoxymethylphosphinic acid; CGP44532, 3-amino-2-hydroxypropylmethylphosphinic acid; CGP54626, [S-(R,R)]-[3-[[1-(3,4-dichlorophenyl)ethyl]amino]-2-hydroxypro-pyl](cyclohexylmethyl)phosphinic acid; CGP55845, 3-[-1-(S)-(3,4-dichlorphenyl)-ethyl]amino-2(S)-hydroxypropyl-(P-benzyl)-phosphinic acid; CGP62349, [3-[1-R-[[3-(methoxyphenylmethyl)hydroxyphosphinyl]-2(5)-hydroxypropyl]amino]ethyl]-benzoic acid; CGP64213, [3-[-(R)-[[3-5N-[1-[2-[[3-iodo-4-hydroxyphenyl]ethyl]carboxamido]pentyl]hydroxyphosphinyl]-2(S)-hydroxy-propyl]amino]ethyl-benzoic acid; CGP71872, 3-(1-(R)-(3-((5-(4-azido-2-hydroxy-5-iodobenzoylamino)pentyl)hydroxyphosphoryl)-2-(S)-hydroxypropylamino)ethyl)benzoic acid; GS39783,N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine; SCH90511, (+)-(2S)-5,5-dimethyl-2-morpholineacetic acid

Further Reading

Bettler B, Kaupmann K, Mosbacher J, Gassmann M (2004). Molecular structure and physiological functions of GABAB receptors. Physiol Rev84: 835–367.

Bettler B, Tiao JY (2006). Molecular diversity, trafficking and subcellular localization of GABAB receptors. Pharmacol Ther110: 533–543.

Bowery NG (2000). Pharmacology of GABAB receptors. In: Möhler H (ed). Handbook of Experimental Pharmacology, Pharmacology of GABA and Glycine Neurotransmission, vol.150, Springer, pp 311–328.

Bowery NG (2006). GABAB receptor: a site of therapeutic benefit. Curr Opin Pharmacol6: 37–43.

Bowery NG, Enna SJ (2000). γ Aminobutyric acidB receptors: first of the functional metabotropic heterodimers. J Pharmacol Exp Ther292: 2–7.

Bowery NG, Bettler B, Froestl W, Gallagher JP, Marshall F, Raiteri M et al. (2002). International Union of Pharmacology XXXIII. Mammalian γ-aminobutyric acidB receptors: structure and function. Pharmacol Rev54: 247–264.

Cryan JF, Kaupmann K (2005). Don't worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends Pharmacol Sci26: 36–43.

Enna SJ, Bowery NG (2004). GABAB receptor alterations as indicators of physiological and pharmacological function. Biochem Pharmacol68: 1541–1548.

Froestl W, Mickel SW (1997). Chemistry of GABAB modulators. In: Enna SJ, Bowery NG (eds). The GABA Receptors. Totowa: Humana Press, pp 271–296.

Hammond DL (2001). GABAB receptors: new tricks by an old dog. Curr Opin Pharmacol1: 26–30.

Kornau HC (2006). GABAB receptors and synaptic modulation. Cell Tissue Res326: 517–533.

Kubo Y, Tateyama M (2005). Towards a view of functioning dimeric metabotropic receptors. Curr Opin Neurobiol15: 289–295.

Marshall FH (2005). Is the GABA B heterodimer a good drug target? J Mol Neurosci26: 169–176.

Pin J-P, Kniazeff J, Binet V, Liu J, Maurel D, Galvez T et al. (2004). Activation mechanism of the heterodimeric GABAB receptor. Biochem Pharmacol68: 1565–1572.

Pin J-P, Neubig R, Bouvier M, Devi L, Filizola M, Javitch JA et al. (2007). International Union of Basic and Clinical Pharmacology. LXVII. Recommendations for the recognition and nomenclature of G protein-coupled receptor heteromultimers. Pharmacol Rev59: 5–13.

References

Adams CL, Lawrence AJ (2007). CNS Drug Rev13: 308–316.

Belley M et al. (1999). Bioorg Med Chem7: 2697–2704.

Bittiger H et al. (1992). Pharmacol Commun2: 23.

Dupuis DS et al. (2006). Mol Pharmacol70: 2027–2036.

Galvez T et al. (2000). Mol Pharmacol57: 419–426.

Gassmann M et al. (2004). J Neurosci42: 6086–6097.

Kier MJ et al. (1999). Brain Res Mol Brain Res71: 279–289.

Pérez-Garci E et al. (2006). Neuron50: 603–616.

Tabata T et al. (2004). Proc Natl Acad Sci USA101: 16952–16957.

Vacher CM et al. (2006). J Neurochem97: 979–991.

Vigot R et al. (2006). Neuron50: 589–601.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Galanin

Overview: Galanin receptors (provisional nomenclature) are activated by the endogenous peptides galanin (ENSG00000069482) and galanin-like peptide (GALP, ENSG00000105099). Human galanin is a 30 amino-acid non-amidated peptide (Evans and Shine, 1991); in other species, it is 29 amino acids long and C-terminally amidated. Amino acids 1–14 of galanin are highly conserved in mammals, birds, reptiles, amphibia and fish. Shorter peptide species (e.g. human galanin-1–19, (Bersani et al., 1991a) and porcine galanin-5–29 (Sillard et al., 1992)) and N-terminally extended forms (e.g. N-terminally seven and nine residue elongated forms of porcine galanin (Bersani et al., 1991b; Sillard et al., 1992)) have been reported.

NomenclatureGAL1GAL2GAL3
Other namesGalanin-1 receptor, GALR1Galanin-2 receptor, GALR2Galanin-3 receptor, GALR3
Ensembl IDENSG00000166573ENSG00000182687ENSG00000128310
Principal transductionGi/oGi/o,Gq/11Gi/o
Rank order of potencyGalanin>GALP (Ohtaki et al., 1999)GALP>galanin (Ohtaki et al., 1999)GALP>galanin (Lang et al., 2005)
Selective agonistsGalanin-(2–29) (Fathi et al., 1997; Wang et al., 1997), D-Trp2-galanin-(1–29) (Smith et al., 1997)
Selective antagonists2,3-Dihydro-dithiin and -dithiepine-1,1,4,4-tetroxides (Scott et al., 2000)M871 (7.9, Sollenberg et al., 2006)

Galanin-(1–11) is a high-affinity agonist at GAL1/GAL2 (pKi 9) and galanin-(2–11) is selective for GAL2 and Gal3 compared to GAL1 (Lu et al., 2005). [125I]-[Tyr26]galanin binds to all three subtypes with Kd values ranging from 0.05 to 1 nM (Skofitsch et al., 1986; Smith et al., 1997, 1998; Wang et al., 1997; Fitzgerald et al., 1998). Porcine galanin-(3–29) does not bind to cloned GAL1, GAL2 or GAL3 receptors, but a receptor that is functionally activated by porcine galanin-(3–29) has been reported in pituitary and gastric smooth muscle cells (Wynick et al., 1993; Gu et al., 1995). Additional galanin receptor subtypes are also suggested from studies with chimeric peptides (e.g M15, M35 and M40), which act as antagonists in functional assays in the cardiovascular system (Ulman et al., 1993), spinal cord (Wiesenfeld-Hallin et al., 1992), locus coeruleus, hippocampus (Bartfai et al., 1991) and hypothalamus (Leibowitz and Kim, 1992; Bartfai et al., 1993), but exhibit agonist activity at some peripheral sites (Bartfai et al., 1993; Gu et al., 1995). The chimeric peptides M15, M32, M35, M40 and C7 are agonists at GAL1 receptors expressed endogenously in Bowes human melanoma cells (Ohtaki et al., 1999), and at heterologously expressed recombinant GAL1, GAL2 and GAL3 receptors (Smith et al., 1997; Fitzgerald et al., 1998; Smith et al., 1998).

Abbreviations: C7, galanin-(1–13)-spantide; M15, galanin-(1–13)-substance P-5-11 amide^also known as galantide; M32, galanin-(1–13)-neuropeptide Y amide-(25–36) amide; M35, galanin-(1–13)-bradykinin-(2–9) amide; M40, galanin-(1–13)-Pro-Pro-Ala-Leu-Ala-Leu-Ala-Leu-Ala amide; M871, galanin-(2–13)-Glu-His-(Pro)3-(Ala-Leu)2-Ala-amide

Further Reading

Gottsch ML, Clifton DK, Steiner RA (2004). Galanin-like peptide as a link in the integration of metabolism and reproduction. Trends Endocrinol Metab15: 215–221.

Jacobowitz DM, Kresse A, Skofitsch G (2004). Galanin in the brain: chemoarchitectonics and brain cartography–a historical review. Peptides25: 433–464.

Lang R, Gundlach AL, Kofler B (2007). The galanin peptide family: receptor pharmacology, pleiotropic biological actions, and implications in health and disease. Pharmacol Ther115: 177–207.

Lu X, Lundstrom L, Langel U, Bartfai T (2005). Galanin receptor ligands. Neuropeptides39: 143–146.

Ogren SO, Kuteeva E, Hokfelt T, Kehr J (2006). Galanin receptor antagonists: a potential novel pharmacological treatment for mood disorders. CNS Drugs20: 633–654.

Walton KM, Chin JE, Duplantier AJ, Mather RJ (2006). Galanin function in the central nervous system. Curr Opin Drug Discov Devel9: 560–570.

References

Bartfai T et al. (1991). Proc Natl Acad Sci USA88: 10961–10965.

Bartfai T et al. (1993). Proc Natl Acad Sci USA90: 11287–11291.

Bersani M et al. (1991a). FEBS Lett283: 189–194.

Bersani M et al. (1991b). Endocrinology129: 2693–2698.

Evans HF, Shine J (1991). Endocrinol129: 1682–1684.

Fathi Z et al. (1997). Mol Brain Res51: 49–59.

Fitzgerald LW et al. (1998). J Pharmacol Exp Ther287: 448–456.

Gu ZF et al. (1995). J Pharmacol Exp Ther272: 371–378.

Lang R et al. (2005). Neuropeptides39: 179–184.

Leibowitz SF, Kim T (1992). Brain Res599: 148–152.

Lu X et al. (2005). Neuropeptides39: 165–167.

Ohtaki T et al. (1999). J Biol Chem274: 37041–37045.

Scott MK et al. (2000). Bioorg Med Chem8: 1383–1391.

Sillard R et al. (1992). Peptides13: 1055–1060.

Skofitsch G et al. (1986). Peptides7: 1029–1042.

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Smith KE et al. (1998). J Biol Chem273: 23321–23326.

Sollenberg UE et al. (2006). Int J Pept Res Ther12: 115–119.

Ulman LG et al. (1993). J Physiol464: 491–499.

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Wiesenfeld-Hallin Z et al. (1992). Proc Natl Acad Sci USA89: 3334–3337.

Wynick D et al. (1993). Proc Natl Acad Sci USA90: 4231–4235.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Ghrelin

Overview: Ghrelin receptors (see Davenport et al., 2005) are activated by a 28 amino-acid peptide originally isolated from rat stomach, where it is cleaved from a 117 amino-acid precursor (ENSG00000157017). The human gene encoding the precursor peptide has 83% sequence homology to rat prepro-ghrelin, although the mature peptides from rat and human differ by only two amino acids (Matsumoto et al., 2001). Alternative splicing results in the formation of a second peptide, des-Gln14-ghrelin with equipotent biological activity (Hosoda et al., 2000). A unique post-translational modification (octanoylation of Ser3) occurs in both peptides, essential for full activity in binding to the ghrelin receptors in the hypothalamus and pituitary; and the release of growth hormone release from the pituitary (Kojima et al., 1999). Structure activity studies showed the first five N-terminal amino acids to be the minimum required for binding (Bednarek et al., 2000).

NomenclatureGhrelin
Other namesGHS-R1a (Growth hormone secretagogue receptor type 1), growth hormone-releasing peptide receptor
Ensembl IDENSG00000121853
Principal transductionGq/11
Rank order of potencyGhrelin = des-Gln-ghrelin (Matsumoto et al., 2001; Bedendi et al., 2003)
Selective antagonistsYIL781 (KB 11 nM) (Esler et al., 2007)
Probes[125I-His9]-ghrelin (0.4 nM, Katugampola et al., 2001), [125I-Tyr4]-ghrelin (0.5 nM, Bedendi et al., 2003), [125I]-Tyr4-des-octanoyl (0.7 nM, Bedendi et al., 2003)

Des-octanoyl ghrelin has been shown to bind (as [125I]-Tyr4-des-octanoyl ghrelin) and have effects in the cardiovascular system (Bedendi et al., 2003), which raises the possible existence of different receptor subtypes in peripheral tissues and the central nervous system. One study has reported constitutive activity of the ghrelin receptor and has identified a potent inverse agonist ([D-Arg1, D-Phe5, D-Trp7,9,Leu11]-substance P, EC50 5.2 nM; Holst et al., 2003).

Abbreviations: YIL781, 6-(4-fluorophenoxy)-3-([(3S)-1-isopropylpiperidin-3-yl]methyl)-2-methylquinazolin-4(3H)-one

Further Reading

Cao JM, Ong H, Chen C (2006). Effects of ghrelin and synthetic GH secretagogues on the cardiovascular system. Trends Endocrinol Metab17: 13–18.

Cummings DE (2006). Ghrelin and the short- and long-term regulation of appetite and body weight. Physiol Behav89: 71–84.

Davenport AP, Bonner TI, Foord SM, Harmar AJ, Neubig RR, Pin JP et al. (2005). International Union of Pharmacology. LVI. Ghrelin receptor nomenclature, distribution, and function. Pharmacol Rev57: 541–546.

De Vriese C, Delporte C (2007). Influence of ghrelin on food intake and energy homeostasis. Curr Opin Clin Nutr Metab Care10: 615–619.

Garcia EA, Korbonits M (2006). Ghrelin and cardiovascular health. Curr Opin Pharmacol6: 142–147.

Hosoda H, Kojima M, Kangawa K (2006). Biological, physiological, and pharmacological aspects of ghrelin. J Pharmacol Sci100: 398–410.

Kojima M, Kangawa K (2005). Ghrelin: structure and function. Physiol Rev85: 495–522.

Kojima M, Kangawa K (2006). Drug insight: The functions of ghrelin and its potential as a multitherapeutic hormone. Nat Clin Pract Endocrinol Metab2: 80–88.

Leite-Moreira AF, Soares JB (2007). Physiological, pathological and potential therapeutic roles of ghrelin. Drug Discov Today12: 276–288.

Maguire JJ, Davenport AP (2005). Regulation of vascular reactivity by established and emerging GPCRs. Trends Pharmacol Sci26: 448–454.

Peeters TL (2006). Potential of ghrelin as a therapeutic approach for gastrointestinal motility disorders. Curr Opin Pharmacol6: 553–558.

Sharma V, McNeill JH (2005). The emerging roles of leptin and ghrelin in cardiovascular physiology and pathophysiology. Curr Vasc Pharmacol3: 169–180.

Smith RG, Jiang H, Sun Y (2005). Developments in ghrelin biology and potential clinical relevance. Trends Endocrinol Metab16: 436–442.

References

Bedendi I et al. (2003). Eur J Pharmacol476: 87–95.

Bednarek MA et al. (2000). J Med Chem43: 4370–4376.

Esler WP et al. (2007). Endocrinology148: 5175–5185.

Holst B et al. (2003). Mol Endocrinol17: 2201–2210.

Hosoda H et al. (2000). J Biol Chem275: 21995–22000.

Katugampola SD et al. (2001). Br J Pharmacol134: 143–149.

Kojima M et al. (1999). Nature402: 656–660.

Matsumoto M et al. (2001). Biochem Biophys Res Commun287: 142–146.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Glucagon, glucagon-like peptide and secretin

Overview: The glucagon family of receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on the Glucagon receptor family, see Mayo et al., 2003) are activated by the endogenous peptide (27–44 aa) hormones glucagon, glucagon-like peptide 1 (GLP-1), glucagon-like peptide 2 (GLP-2), glucose-dependent insulinotropic polypeptide (also known as gastric inhibitory polypeptide or GIP, ENSG00000159224), growth hormone-releasing hormone (GHRH, ENSG00000118702) and secretin (ENSG00000070031). One common precursor (ENSG00000115263) generates glucagon, GLP-1 and GLP-2 peptides (Irwin, 2001).

NomenclatureGlucagonGLP-1GLP-2
Ensembl IDENSG00000141558ENSG00000112164ENSG00000065325
Principal transductionGsGsGs
Selective agonistsGlucagonGLP-1-(7-37) (Dillon et al., 1993); GLP-1-(7-36)amide (Thorens et al., 1993), exendin-3 (Raufman et al., 1991), exendin-4 (Thorens et al., 1993)GLP-2
Selective antagonistsL168049 (Cascieri et al., 1999), des-His1-[Glu9]glucagon amide (Post et al., 1993), BAY27-9955 (Petersen and Sullivan, 2001), NNC92-1687 (Madsen et al., 1998)Exendin-(9-39) (Thorens et al., 1993); T0632 (Tibaduiza et al., 2001)
Probes[125I]-glucagon[125I]-GLP-1-(7-36) amide, [125I]-exendin, [125I]-exendin-(9-39), [125I]-GLP-1-(7-37)
NomenclatureGIPGHRHSecretin
Ensembl IDENSG00000010310ENSG00000106128ENSG00000080293
Principal transductionGsGsGs
Selective agonistsGIPBIM28011 (Coy et al., 1996)Secretin
Selective antagonistsJV-1-36 (Schally and Varga, 1999), JV-1-38 (Schally and Varga, 1999)[(CH2NH)4,5]secretin (Kim et al., 1993)
Probes[125I]-GIP[125I]-GHRH[125I]-(Tyr10)secretin

The glucagon receptor has been reported to interact with receptor activity modifying proteins (RAMPs), specifically RAMP2, in heterologous expression systems (Christopoulos et al., 2003), although the physiological significance of this has yet to be established.

Abbreviations: BAY27-9955, (+)-3,5-diiospropyl-2-(1-hydroxyethyl)-6-propyl-4′-fluoro-1,1′-biphenyl; BIM28011, [D-Ala2,Ala8,9,15,27,D-Arg29]hGHRH-(1–29)NH2; JV-1-36, [PhAc-Tyr1,D-Arg2,Phe(4-Cl)6,Arg9,Abu15, Nle27,D-Arg28,Har29]hGHRH(1–29)NH2; JV-1-38, [PhAc-Tyr1,D-Arg2,Phe(4-Cl)6,Har9,Tyr(Me)10, Abu15, Nle27, D-Arg28, Har29]hGHRH(1–29)NH2; L168049, 2-(4-pyridyl)-5-(4-chlorophenyl)-3-(5-bromo-2-propyl-oxyphenyl)pyrrole; NNC92-1687, 2-(benzimidazol-2-ylthio)-1-(3,4-dihydroxyphenyl)-1-ethanone|T0632, sodium (S)-3-(1-[2-fluorophenyl]-2, 3-dihydro-3-[{3-isoquinolinyl}-carbonyl]amino-6-methoxy-2-oxo-1H-indole)propanoate

Further Reading

Burcelin R (2005). The incretins: a link between nutrients and well-being. Br J Nutr93 (Suppl 1): S147–S156.

D'Alessio DA, Vahl TP (2004). Glucagon-like peptide 1: evolution of an incretin into a treatment for diabetes. Am J Physiol-Endocrinol Metab286: E882–E890.

De Leon DD, Crutchlow MF, Ham JY, Stoffers DA (2006). Role of glucagon-like peptide-1 in the pathogenesis and treatment of diabetes mellitus. Int J Biochem Cell Biol38: 845–859.

Doyle ME, Egan JM (2007). Mechanisms of action of glucagon-like peptide 1 in the pancreas. Pharmacol Ther113: 546–593.

Estall JL, Drucker DJ (2006). Glucagon-like Peptide-2. Annu Rev Nutr26: 391–411.

Frezza EE, Wachtel MS, Chiriva-Internati M (2007). The multiple faces of glucagon-like peptide-1—obesity, appetite, and stress: what is next? A review. Dig Dis Sci52: 643–649.

Gromada J, Brock B, Schmitz O, Rorsman P (2004). Glucagon-like peptide-1: regulation of insulin secretion and therapeutic potential. Basic Clin Pharmacol Toxicol95: 252–262.

Gutzwiller JP, Degen L, Heuss L, Beglinger C (2004). Glucagon-like peptide 1 (GLP-1) and eating. Physiol Behav82: 17–19.

Keller G, Schally AV, Groot K, Toller GL, Havt A, Koster F et al. (2005). Effective treatment of experimental human non-Hodgkin's lymphomas with antagonists of growth hormone-releasing hormone. Proc Natl Acad Sci USA102: 10628–10633.

Knudsen LB (2004). Glucagon-like peptide-1: the basis of a new class of treatment for type 2 diabetes. J Med Chem47: 4128–4134.

List JF, Habener JF (2004). Glucagon-like peptide 1 agonists and the development and growth of pancreatic β-cells. Am J Physiol-Endocrinol Metab286: E875–E881.

Mayo KE, Miller LJ, Bataille D, Dalle S, Goke B, Thorens B et al. (2003). International Union of Pharmacology. XXXV. The glucagon receptor family. Pharmacol Rev55: 167–194.

Nielsen LL (2005). Incretin mimetics and DPP-IV inhibitors for the treatment of type 2 diabetes. Drug Discov Today10: 703–710.

Siu FK, Lam IP, Chu JY, Chow BK (2006). Signaling mechanisms of secretin receptor. Regul Pept137: 95–104.

Stanley S, Wynne K, Bloom S (2004). Gastrointestinal satiety signals III. Glucagon-like peptide 1, oxyntomodulin, peptide YY, and pancreatic polypeptide. Am J Physiol -Gastrointest Liver Physiol286: G693–G697.

Urusova IA, Farilla L, Hui H, D'Amico E, Perfetti R (2004). GLP-1 inhibition of pancreatic islet cell apoptosis. Trends Endocrinol Metab15: 27–33.

References

Cascieri MA et al. (1999). J Biol Chem274: 8694–8697.

Christopoulos A et al. (2003). J Biol Chem278: 3293–3297.

Coy DH et al. (1996). Ann N Y Acad Sci805: 149–158.

Dillon JS et al. (1993). Endocrinology133: 1907–1910.

Irwin DM (2001). Regul Pept98: 1–12.

Kim CD et al. (1993). Am J Physiol -Gastrointest Liver Physiol265: G805–G810.

Madsen P et al. (1998). J Med Chem41: 5150–5157.

Petersen KF, Sullivan JT (2001). Diabetologia44: 2018–2024.

Post SR et al. (1993). Proc Natl Acad Sci USA90: 1662–1666.

Raufman JP et al. (1991). J Biol Chem266: 2897–2902.

Schally AV, Varga JL (1999). Trends Endocrinol Metab10: 383–391.

Thorens B et al. (1993). Diabetes42: 1678–1682.

Tibaduiza EC et al. (2001). J Biol Chem276: 37787–37793.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Glutamate, metabotropic

Overview: Metabotropic glutamate (mGlu) receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Metabotropic Glutamate Receptors, Schoepp et al., 2000) are activated by the endogenous ligands L-glutamate, L-aspartate, L-serine-O-phosphate (LSOP), N-acetylaspartylglutamate (NAAG) and L-cysteine sulphonic acid. Examples of agonists selective for mGlu receptors compared with ionotropic glutamate receptors are 1S,3R-ACPD and L-CCG-I, which show limited selectivity for Group II receptors. An example of an antagonist selective for mGlu receptors is LY341495, which blocks mGlu2 and mGlu3 at low nanomolar concentrations, mGlu8 at high nanomolar concentrations, and mGlu1, mGlu4, mGlu5 and mGlu7 in the micromolar range (Kingston et al., 1998). Currently, three groups of native receptors are distinguishable on the bases of similarities of agonist pharmacology, primary sequence and G-protein effector coupling: Group I (mGlu1 and mGlu5); Group II (mGlu2 and mGlu3) and Group III (mGlu4, mGlu6, mGlu7 and mGlu8) (see Further reading). Group I mGlu receptors may be activated by DHPG and 3HPG (Brabet et al., 1995), and antagonized by LY393675 (Baker et al., 1998). Group II mGlu receptors may be activated by LY389795 (Monn et al., 1999), LY379268 (Monn et al., 1999), LY354740 (Schoepp et al., 1997; Wu et al., 1998), DCG-IV and 2R,4R-APDC (Schoepp et al., 1996), and antagonised by EGLU (4.3, Jane et al., 1996) and LY307452 (Wermuth et al., 1996; Escribano et al., 1998). Group III mGlu receptors may be activated by (RS)PPG (Gasparini et al., 1999a).

In addition to orthosteric ligands that directly interact with the glutamate recognition site, allosteric modulators have been described. Negative allosteric modulators are listed separately. The positive allosteric modulators most often act as ‘potentiators’ of an orthosteric agonist response, without significantly activating the receptor in the absence of agonist. Examples of these unique pharmacological agents have been described for mGlu1, mGlu2, mGlu4 and mGlu5.

NomenclaturemGlu1mGlu2mGlu3mGlu4
Other namesmGluR1mGluR2mGluR3mGluR4
Ensembl IDENSG00000152822ENSG00000164082ENSG00000105781ENSG00000124493
Principal transductionGq/11G1/oG1/oG1/o
Selective agonistsNAAG (Wroblewska et al., 1997)L-AP4, LSOP (Wu et al., 1998),
Selective positive allosteric modulatorsRo01-6128, Ro67-4853, Ro67-7476 (Knoflach et al., 2001)LY487379 (Johnson et al., 2003), CBiPES (Johnson et al., 2005)(—)—PHCCC (Maj et al., 2003), SIB1893, MPEP (Mathiesen et al., 2003)
Selective competitive antagonists3-MATIDA (Moroni et al., 2002), AIDA (Moroni et al., 1997), (S)-(+)-CBPG (Mannaioni et al., 1999), LY367385 (Clark et al., 1997), (S)-TBPG (Costantino et al. 2001)PCCG-4 (Pellicciari et al., 1996)MAP4
Selective negative allosteric modulatorsCPCCOEt (Litschig et al., 1999), BAY36-7620 (Carroll et al., 2001), LY456236 (Li et al., 2002), 3,5-DMPPP (Micheli et al., 2003), EM-TBPC (Malherbe et al., 2003), JNJ16259685 (Lavreysen et al., 2004)
NomenclaturemGlu5mGlu6mGlu7mGlu8
Other namesmGluR5mGluR6mGluR7mGluR8
Ensembl IDENSG00000168959ENSG00000113262ENSG00000168160ENSG00000179603
Principal transductionGq/11Gi/oGi/oGi/o
Selective agonistsCHPG (Doherty et al., 1997), (S)-(+)-CBPG (Mannaioni et al., 1999)Homo-AMPA (Bräuner-Osborne et al., 1996), 1-benzyl-APDC (Tuckmantel et al., 1997)LSOP (Wu et al., 1998), L-AP4LSOP (Wu et al., 1998), L-AP4, (S)-3,4-DCPG (Thomas et al., 2001)
Selective positive allosteric modulatorsDFB (O'Brien et al., 2003), CPPHA (O'Brien et al., 2004), CDPPB (Kinney et al., 2005)AMN082 (Flor et al., 2005)
Selective competitive antagonistsACDPP (6.5, Bonnefous et al., 2005)MAP4, THPG (Thoreson et al., 1997)MPPG (Wu et al., 1998)
Selective negative allosteric modulatorsSIB1757 (Varney et al., 1999), SIB1893 (Varney et al., 1999), MPEP (Gasparini et al., 1999b), MTEP (Brodkin et al., 2002), fenobam (Porter et al., 2005), YM298198 (Kohara et al., 2005)

Radioligand binding using a variety of radioligands has been conducted on recombinant receptors (for example, [3H]-R214127 (Lavreysen et al., 2003) and [3H]-YM298198 (Kohara et al., 2005) at mGlu1 receptors and [3H]-methoxyMPEP (Gasparini et al., 2002) and [3H]-methoxymethyl-MTEP (Anderson et al., 2002) at mGlu5 receptors. Although a number of radioligands have been used to examine binding using native tissues, correlation with individual subtypes is limited. Many pharmacological agents have not been fully tested across all known subtypes of mGlu receptors. Potential differences linked to the species (e.g. human versus rat or mouse) of the receptors and the receptor splice variants are generally not known. The influence of receptor expression level on pharmacology and selectivity has not been controlled for in most studies, particularly those involving functional assays of receptor coupling.

(S)-(+)-CBPG is an antagonist at mGlu1, but is an agonist (albeit of reduced efficacy) at mGlu5 receptors. DCG-IV also exhibits agonist activity at NMDA glutamate receptors (Uyama et al., 1997). A potential novel metabotropic glutamate receptor coupled to phosphoinositide turnover has been observed in rat brain; it is activated by 4-methylhomoibotenic acid (ineffective as an agonist at recombinant Group I metabotropic glutamate receptors), but resistant to LY341495 (Chung et al., 1997). There are also reports of a novel metabotropic glutamate receptor coupled to phospholipase D in rat brain, which does not readily fit into the current classification (Pellegrini-Giampietro et al., 1996; Klein et al., 1997).

Abbreviations: 1S,3R-ACPD, 1-aminocyclopentane-1S,3R-dicarboxylate; AIDA, 1-aminoindan-1,5(RS)-dicarboxylic acid; also known as UPF523; AMN082,N,N'-bis(diphenylmethyl)-1,2-ethanediamine dihydrochloride; L-AP4,S-2-amino-4-phosphonobutyrate; 2R,4R-APDC, aminopyrrolidine-2R,4R-dicarboxylate;also known as LY314593; BAY 36-7620, (3aS,6aS)-6a-naphtalan-2-ylmethyl-5-methyliden-hexahyrol-cyclopenta[c]furan-1-one; CBiPES,N-[4’-cyano-biphenyl-3-yl]-N-(3-pyridinylmethyl)-ethanesulphonamide hydrochloride; (S)-(+)-CBPG, (s)-(1)-2-(39-carboxybicycle[1.1.1]pentyl)glycine; L-CCG-I, (2S,3S,4S)α-(carboxycyclopropyl)glycine; CDPPB, 3-cyano-N-(1,3-diphenyl-1H-[pyrazol-5-yl)benzamide; CHPG, 2-chloro-5-hydroxyphenylglycine; CPCCOEt, cyclopropan[b]chromen-1a-carboxylate; 4CPG, 4-carboxyphenyl-glycine; CPPHA,N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide; DCG-IV, (2S,1′R,2′R,3′R)-2-(2,3-dicarboxycyclopropyl)glyciye; (S)-3,4-DCPG, (S)-3,4-dicarboxylphenylglycine; DFB, 3,3′-difluorobenzaldazine; DHPG,S-3,5-dihydroxy-phenylglycine; DMPPP, 3,5-dimethyl pyrrole-2,4-dicarboxylic acid 2-propyl ester 4-(1,2,2-tri-methyl-propyl) ester; EGLU, (s)α-ethylglutamate; fenobam,N-(3-chlorophenyl)-N'-(4,5-dihydrol-1-methyl-4-oxo-1-H-imidazole-2-yl)-urea; 3HPG, 3-hydroxyphenylglycine; [11C]-JNJ-16567083, (3-ethyl-2-[11C]methyl-6-quinolinyl)(cis-4-methoxycyclohexyl) methanone; JNJ16259685, (3,4-dihydro-2H-pyrano[2,3]b-quinolinyl-7-yl)(cis-4-methoxycyclohexyl)methanone; LY307452, 2S,4S-2-amino-4-(4,4-diphenylbut-1-yl)pentan-1,5-dioc acid; LY341495, 2S-2-amino-2-(1S,2S-2-carboxycyclopropan-1-yl)-3-(xanth-9-yl)propanoic acid; LY354740, (+)-2-aminobicyclic[3.1.0]hexane-2,6-dicarboxylate; LY367385, (+)-2-methyl-4-carboxyphenylglycine; LY379268, (-)-2-oxa-4-aminobicylco[3.1.0]hexane-4,6-dicarboxylic acid; LY389795, (-)-2-thia-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylic acid; LY393675, α-substituted-cyclobutylglycine; LY456066, (2-[4-(indan-2-ylamino)-5,6,7,8-tetrahydro-quinazolin-2-ylsulfanyl]-ethanol,hydrochloride; LY456236, [(4-methoxy-phenyl)-(6-methoxy-quinazolin-4-yl)-amine hydrochloride; LY487379, 2,2,2-trifluoro-N-[4-(2-methoxyphenoxy)phenyl]-N-(3-pyridinylmetmyl)-ethanesulphonamide; 3-MATIDA, α-amino-5-carboxy-3-methyl-2-thiopheneacetic acid; MAP4, (S)-2-methyl-2-amino-4-phosphonobutanoate; MPEP, 2-methyl-6-(phenylethynyl)-pyridine; methoxy-MPEP, 2-methyl-6-((3-methoxyphenyl)ethynyl)-pyridine; methoxy-PEPy, 3-methoxy-5-(pyridin-2-yl-ethynyl)-pyridine; MPPG, (RS)-α-methyl-4-phosphonophenylglycine; MTEP, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine; methoxymethyl-MTEP, 3-(methoxymethyl)-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine; NAAG,N-acetylaspartylglutamate, also known as spaglumic acid; PCCG-4, (2S,1′S,2′S,3′R)-2-(2′-carboxy-3′-phenylcyclopropyl)glycine; PHCCC,N-phenyl-7-(hydroxylimino)cyclopropa[b]chromen-1a-carboxamide; (RS)PPG, (R,S)-4-phos-phonophenylglycine; R214127, 1-(3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-2-phenyl-1-ethanone; Ro01-6128, diphenylacetyl-carbamic acid ethyl ester; Ro67-4853, (9H-xanthene-9-carbonyl)-carbamic acid butyl ester; Ro67-7476, (S)-2-(4-fluoro-phenyl)-1-(toluene-4-sulphonyl)-pyrrolidine; SIB1757, 6-methyl-2-(phenylazo)-3-pyrindol; SIB1893, ([phenylazo]-3-pyrindole)-2-methyl-6-(2-phenylethenyl)pyridine; S-TBPG, 2-(3′-(1H-tetrazol-5-yl)bicyclo[1.1.1]pent-1-yl)glycine; THPG, (RS)-3,4,5-trihydroxyphenylglycine; YM298198, (6-{[(2-methoxyethyl)amino]methyl}-N-methyl-N-neopentylthiaolo[3,2-a]benzoimidazole-2-carboxamide

Further Reading

Dhami GK, Ferguson SS (2006). Regulation of metabotropic glutamate receptor signaling, desensitization and endocytosis. Pharmacol Ther111: 260–271.

Ferraguti F, Shigemoto R (2006). Metabotropic glutamate receptors. Cell Tissue Res326: 483–504.

Gerber U, Gee CE, Benquet P (2007). Metabotropic glutamate receptors: intracellular signaling pathways. Curr Opin Pharmacol7: 56–61.

Kubo Y, Tateyama M (2005). Towards a view of functioning dimeric metabotropic receptors. Curr Opin Neurobiol15: 289–295.

Marino MJ, Conn PJ (2006). Glutamate-based therapeutic approaches: allosteric modulators of metabotropic glutamate receptors. Curr Opin Pharmacol6: 98–102.

Schkeryantz JM, Kingston AE, Johnson MP (2007). Prospects for metabotropic glutamate 1 receptor antagonists in the treatment of neuropathic pain. J Med Chem50: 2563–2568.

Schoepp DD, Alexander SP, Beart P, Conn PJ, Lodge D, Nakanishi S et al. (2000). Metabotropic glutamate receptors. In: Watson SP, Girdlestone (eds). The IUPHAR Compendium of Receptor Characterization and Classification, 2nd edn. IUPHAR Press: London.

Swanson CJ, Bures M, Johnson MP, Linden AM, Monn JA, Schoepp DD (2005). Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nat Rev Drug Discovery4: 131–144.

Ure J, Baudry M, Perassolo M (2006). Metabotropic glutamate receptors and epilepsy. J Neurol Sci247: 1–9.

References

Anderson JJ et al. (2002). J Pharmacol Exp Ther303: 1044–1051.

Baker RS et al. (1998). Society for Neuroscience Abstracts.

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Brabet I et al. (1995). Neuropharmacology34: 895–903.

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Carroll FY et al. (2001). Mol Pharmacol59: 965–973.

Chung DS et al. (1997). J Pharmacol Exp Ther283: 742–749.

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Doherty AJ et al. (1997). Neuropharmacology36: 265–267.

Escribano A et al. (1998). Bioorg Med Chem Lett8: 765–770.

Flor PJ et al. (2005). Neuropharmacology47: 244.

Gasparini F et al. (1999a). J Pharmacol Exp Ther289: 1678–1687.

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Gasparini F et al. (2002). Bioorg Med Chem Lett12: 407–409.

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Johnson MP et al. (2003). J Med Chem46: 3189–3192.

Johnson MP et al. (2005). Psychopharmacol179: 271–283.

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Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Glycoprotein hormone

Overview: Glycoprotein hormone receptors (provisional nomenclature) are activated by a heterodimeric glycoprotein made up of a common α chain (116 amino-acid ENSG00000135346), with a unique β chain that confers the biological specificity to FSH (follicle-stimulating hormone, follitropin, 129 amino-acid, ENSG00000131808), LH (luteinizing hormone, lutropin, 141 amino-acid ENSG00000104826), CG (choriogonadotropin, chorionic gonadotropin, 165 amino-acid, ENSG00000104818/ENSG00000104827) or TSH (thyrotropin, thyroid-stimulating hormone, 138 amino-acid ENSG00000134200). There is binding cross-reactivity across the endogenous agonists for each of the glycoprotein hormone receptors. The deglycosylated hormones appear to exhibit reduced efficacy at these receptors (Sairam, 1989).

NomenclatureFSHLHTSH
Ensembl IDENSG00000170820ENSG00000168546ENSG00000146013
Principal transductionGsGs, Gq/11 and GiAll four of Gi-proteins can be activated by this receptor
Selective agonistsFSHLH, CGTSH
Probes[125I]-FSH[125I]-LH, [125I]-CG[125I]-TSH

Animal follitropins are less potent than the human hormone as agonists at the human FSH receptor. Autoimmune antibodies that act as agonists of the TSH receptor are found in patients with Grave's disease (see Rapoport et al., 1998). Gain- and loss-of-function mutations of the FSH receptor are associated with human reproductive disorders (Aittomaki et al., 1995; Gromoll et al., 1996; Beau et al., 1998; Touraine et al., 1999). Loss-of-function mutations of the LH receptor are associated with Leydig cell hypoplasia and gain-of-function mutations are associated with male-limited gonadotropin-independent precocious puberty (e.g. Latronico and Segaloff, 1999; Shenker, 2002) and Leydig cell tumours (Liu et al., 1999). Mutations of the TSH receptor exhibiting constitutive activity underlie hyperfunctioning thyroid adenomas (Parma et al., 1993) and congenital hyperthyroidism (Kopp et al., 1995). TSH receptor loss-of-function mutations are associated with thyrotropin resistance (Sunthornthepvarakul et al., 1995). The rat FSH receptor also stimulates phosphoinositide turnover through an unidentified G protein (Quintana et al., 1994).

Further Reading

Davies TF, Ando T, Lin RY, Tomer Y, Latif R (2005). Thyrotropin receptor-associated diseases: from adenomata to Graves disease. J Clin Invest115: 1972–1983.

Farid NR, Szkudlinski MW (2004). Structural and functional evolution of the thyrotropin receptor. Endocrinology145: 4048–4057.

Hermann BP, Heckert LL (2007). Transcriptional regulation of the FSH receptor: new perspectives. Mol Cell Endocrinol260–262: 100–108.

Latronico AC, Arnhold IJ (2006). Inactivating mutations of LH and FSH receptors–from genotype to phenotype. Pediatr Endocrinol Rev4: 28–31.

Piersma D, Verhoef-Post M, Berns EM, Themmen AP (2007). LH receptor gene mutations and polymorphisms: an overview. Mol Cell Endocrinol260–262: 282–286.

Rao CV, Lei ZM (2007). The past, present and future of nongonadal LH/hCG actions in reproductive biology and medicine. Mol Cell Endocrinol269: 2–8.

Schott M, Scherbaum WA, Morgenthaler NG (2005). Thyrotropin receptor autoantibodies in Graves’ disease. Trends Endocrinol Metab16: 243–248.

Vassart G, Pardo L, Costagliola S (2004). A molecular dissection of the glycoprotein hormone receptors. Trends Biochem Sci29: 119–126.

Ziecik AJ, Kaczmarek MM, Blitek A, Kowalczyk AE, Li X, Rahman NA (2007). Novel biological and possible applicable roles of LH/hCG receptor. Mol Cell Endocrinol269: 51–60.

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Aittomaki K et al. (1995). Cell82: 959–968.

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Latronico AC, Segaloff DL (1999). Am J Hum Genet65: 949–958.

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Parma J et al. (1993). Nature365: 649–651.

Quintana J et al. (1994). J Biol Chem269: 8772–8779.

Rapoport B et al. (1998). Endocr Rev19: 673–716.

Sairam MR (1989). FASEB J3: 1915–1926.

Shenker A (2002). Receptors Channels8: 3–18.

Sunthornthepvarakul T et al. (1995). N Engl J Med332: 155–160.

Touraine P et al. (1999). Mol Endocrinol13: 1844–1854.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Gonadotropin-releasing hormone (GnRH)

Overview: Gonadotropin-releasing hormone (GnRH) is a hypothalamic decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pr-Gly-NH2, also known as luteinising hormone-releasing hormone, gonadoliberin, luliberin, gonadorelin, ENSG00000147437) designated GnRH I, to distinguish it from related peptides such as GnRH II (pGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Plo-Gly-NH2, also known as chicken GnRH-II, ENSG00000180290) and GnRH III (pGlu-His-Trp-Ser-His-Asp-Trp-Lys-Pro-Gly-NH2 also known as lamprey GnRH III). Receptors for all three ligands exist in amphibians but only GnRH I and GnRH II (and their cognate receptors) have been found in mammals (Sealfon et al., 1997; Millar, 2002). Type I and Type II GnRH receptors (provisonal nomenclature) have been cloned from numerous species (most of which express two or three types of GnRHR) and grouped phylogenetically (Silver et al., 2005). Type I GnRHRs are expressed primarily by pituitary gonadotrophs in mammals and mediate central control of reproduction. They are selectively activated by GnRH I and all lack the C-terminal tails found in other seven transmembrane region receptors. Type II GnRHRs include all non-mammalian GnRHRs as well as the recently cloned type II primate GnRHRs. They all possess C-teminal tails and (where tested) are selective for GnRH II (over GnRH I). An alternative phylogenetic classification (see Millar et al., 2004) divided these receptors into three classes and includes both GnRH I-selective mammalian type I GnRHRs and GnRH II-selective non-mammalian receptors in type I. Although thousands of peptide analogues of GnRH I have been synthesised and several (agonists and antagonists) are used therapeutically (Kiesel et al., 2002), the potency of most of these peptides at type II GnRHRs is unknown.

NomenclatureType I GnRHRType II GnRHR
Other namesLHRH receptor, GnRH I receptor
Ensembl IDENSG00000109163ENSG00000180290
Principal transductionGq/11Gq/11
Rank order of potencyGnRH I>GnRH IIGnRH II>GnRH I
Selective agonistsTriptorelin, buserelin, leuprorelin, nafarelin, histrelin, goserelin
Selective antagonistsAntide (9.0, Neill, 2002), cetrorelix (8.8, Neill, 2002), ganirelix, abarelixTrptorelix-1 (Maiti et al., 2003)
Probes[125I]-GnRH I, [125I]-buserelin[125I]-GnRH II

Type I (and type II) GnRHRs couple primarily to Gq/11 (Grosse et al., 2000) but coupling to Gs and Gi is evident in some systems (Krsmanovic et al., 2003). Type II GnRHRs may also mediate (heterotrimeric) G protein-independent signalling to protein kinases (see Caunt et al., 2006). There is increasing evidence for expression of GnRHRs on hormone-dependent cancer cells where they can exert antiproliferative and/or proapoptotic effects and mediate effects of cytotoxins conjugated to GnRH analogues (Limonta et al., 2003; Harrison et al., 2004; Schally and Nagy, 2004; Cheng and Leung, 2005). In some human cancer cell models GnRH II is more potent than GnRH I, implying mediation by a type II GnRHR (Grundker et al., 2002). However, type II GnRHRs that are expressed by some primates are probably not expressed in humans because the human type II GnRHR gene contains a frame shift and internal stop codon (Morgan et al., 2003). The possibility remains that this gene expresses type II GnRHR-related proteins (other than the full-length receptor) that mediate responses to GnRH II (see Neill et al., 2004). Alternatively, there is evidence for multiple active GnRHR conformations (Caunt et al., 2004; Maudsley et al., 2004; Millar et al., 2004) raising the possibility that type I GnRHR-mediated proliferation inhibition in hormone-dependent cancer cells is dependent upon different conformations (with different ligand specificity) than effects on Gq/11 in pituitary cells (Maudsley et al., 2004). Loss-of-function mutations in the type I GnRHR and deficiency of GnRH I are associated with hypogonadotropic hypogonadism although some ‘loss of function’ mutations may actually prevent trafficking of ‘functional’ type I GnRHRs to the cell surface, as evidenced by recovery of function by nonpeptide antagonists (Leanos-Miranda et al., 2003). GnRHR signalling may be dependent upon receptor oligomerisation (Conn et al., 1982; Kroeger et al., 2001).

Further Reading

Caunt CJ, Finch AR, Sedgley KR, McArdle CA (2006). GnRH receptor signalling to ERK: kinetics and compartmentalization. Trends Endocrinol Metab17: 308–313.

Cheng CK, Leung PC (2005). Molecular biology of gonadotropin-releasing hormone (GnRH)-I, GnRH-II, and their receptors in humans. Endocr Rev26: 283–306.

Hapgood JP, Sadie H, van BW, Ronacher K (2005). Regulation of expression of mammalian gonadotrophin-releasing hormone receptor genes. J Neuroendocrinol17: 619–638.

Millar RP (2005). GnRHs and GnRH receptors. Anim Reprod Sci88: 5–28.

Millar RP, Lu ZL, Pawson AJ, Flanagan CA, Morgan K, Maudsley SR (2004). Gonadotropin-releasing hormone receptors. Endocr Rev25: 235–275.

Neill JD, Musgrove LC, Duck LW (2004). Newly recognized GnRH receptors: function and relative role. Trends Endocrinol Metab15: 383–392.

Shah BH, Catt KJ (2004). Matrix metalloproteinases in reproductive endocrinology. Trends Endocrinol Metab15: 47–49.

Whitlock KE (2005). Origin and development of GnRH neurons. Trends Endocrinol Metab16: 145–151.

References

Caunt CJ et al. (2004). Endocrinology145: 3594–3602.

Conn PM et al. (1982). Endocrinology111: 335–337.

Grosse R et al. (2000). J Biol Chem275: 9193–9200.

Grundker C et al. (2002). Am J Obstet Gynecol187: 528–537.

Harrison GS et al. (2004). Endocr Relat Cancer11: 725–748.

Kiesel LA et al. (2002). Clin Endocrinol56: 677–687.

Kroeger KM et al. (2001). J Biol Chem276: 12736–12743.

Krsmanovic LZ et al. (2003). Proc Natl Acad Sci USA100: 2969–2974.

Leanos-Miranda A et al. (2003). J Clin Endocrinol Metab88: 3360–3367.

Limonta P et al. (2003). Front Neuroendocrinol24: 279–295.

Maiti K et al. (2003). Mol Cells16: 173–179.

Maudsley S et al. (2004). Cancer Res64: 7533–7544.

Morgan K et al. (2003). Endocrinology144: 423–436.

Neill JD (2002). Endocrinology143: 737–743.

Schally AV, Nagy A (2004). Trends Endocrinol Metab15: 300–310.

Sealfon SC et al. (1997). Endocr Rev18: 180–205.

Silver MR et al. (2005). Endocrinology146: 3351–3361.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

G-protein-coupled estrogen (GPE)

Overview: The G-protein-coupled estrogen receptor (GPE, provisional nomenclature) was identified following observations of estrogen-evoked cyclic AMP signalling in breast cancer cells (Aronica et al., 1994), which mirrored the differential expression of an orphan 7-transmembrane receptor GPR30 (Carmeci et al., 1997). There are observations of both cell-surface and intracellular expression of the GPE receptor (Revankar et al., 2005; Thomas et al., 2005).

NomenclatureGPE
Other namesGPR30, IL8-related receptor DRY12, flow-induced endothelial G-protein coupled receptor, GPCR-BR, CMKRL2 (Owman et al., 1996)
Ensembl IDENSG00000164850
Principal transductionGs (Filardo et al., 2000), Gi/o (Revankar et al., 2005)
Selective agonistsG1 (Bologa et al., 2006)
Probes[3H]-Estrogen (Revankar et al., 2005)

Antagonists at the nuclear estrogen receptor, such as ICI182780 and tamoxifen (Filardo et al., 2000), as well as the flavonoid ‘phytoestrogens’ genistein and quercetin (Maggiolini et al., 2004), are agonists at GPE receptors.

Abbreviations: G1, 1-(4-[6-bromo-benzo{1,3]dioxol-5-yl}-3a,4,5,9b-tetrahydro-3Hcyclopenta[c]quinolin-8-yl)ethanone; ICI182780, 7α-(9-[{4,4,5,5,5,-pentafluoropentyl}sulphinyl]nonyl)estra-1,3,5(10)-triene-3,17β-diol

Further Reading

Filardo EJ, Thomas P (2005). GPR30: a seven-transmembrane-spanning estrogen receptor that triggers EGF release. Trends Endocrinol Metab16: 362–367.

Hasbi A, O'Dowd BF, George SR (2005). A G protein-coupled receptor for estrogen: the end of the search? Mol Interv5: 158–161.

Manavathi B, Kumar R (2006). Steering estrogen signals from the plasma membrane to the nucleus: two sides of the coin. J Cell Physiol207: 594–604.

Prossnitz ER, Arterburn JB, Sklar LA (2007). GPR30: A G protein-coupled receptor for estrogen. Mol Cell Endocrinol265–266: 138–142.

Smith HO, Leslie KK, Singh M, Qualls CR, Revankar CM, Joste NE et al. (2007). GPR30: a novel indicator of poor survival for endometrial carcinoma. Am J Obstet Gynecol196: 386–389.

References

Aronica SM et al. (1994). Proc Natl Acad Sci USA91: 8517–8521.

Bologa CG et al. (2006). Nat Chem Biol2: 207–212.

Carmeci C et al. (1997). Genomics45: 607–617.

Filardo EJ et al. (2000). Mol Endocrinol14: 1649–1660.

Maggiolini M et al. (2004). J Biol Chem279: 27008–27016.

Owman C et al. (1996). Biochem Biophys Res Commun228: 285–292.

Revankar CM et al. (2005). Science307: 1625–1630.

Thomas P et al. (2005). Endocrinology146: 624–632.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Histamine

Overview: Histamine receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Histamine Receptors, see Hill et al., 1997) are activated by the endogenous ligand histamine. Marked species differences exist between histamine receptor orthologues (see Hill et al., 1997).

NomenclatureH1H2H3H4
Ensembl IDENSG00000171088ENSG00000168546ENSG00000146013ENSG00000125861
Principal transductionGq/11GsGi/oGi/o
Selective agonistsHistaprodifen, Nτ-methylhistaprodifenAmthamineMethimmepip (Kitbunnadaj et al., 2005),Clobenpropit, 4-methylhistamine, VUF8430 (Lim et al., 2006)
Selective antagonistsTriprolidine (9.9), mepyramine (9.1)Tiotidine (7.8), ranitidine (7.1)Clobenpropit (9.9), iodophenpropit (9.6), A331440 (8.5, Hancock et al. 2004), thioperamide (8.4)JNJ7777120 (8.1)
Probes[3H]-Mepyramine (1nM), [11C]-mepyramine, [11C]-doxepin[3H]-Tiotidine (15 nM), [125I]-iodoaminopotentidine (0.3 nM)[3H]-R-α-Methylhistamine (0.5 nM), [3H]-Nα-methylhistamine (2 nM), [125I]-iodophenpropit (0.6 nM), [125I]-iodoproxyfan (0.06 nM)[3H]-JNJ7777120 (3.6 nM)

Histaprodifen and Nτ-methylhistaprodifen are reduced efficacy agonists. The H4 receptor appears to exhibit broadly similar pharmacology to the H3 receptor for imidazole-containing ligands, although R-α-methylhistamine and N-α-methylhistamine are less potent, while clobenpropit acts as a reduced efficacy agonist (Nakamura et al., 2000; Oda et al., 2000; Liu et al., 2001; Nguyen et al., 2001; Zhu et al., 2001). Moreover, 4-methylhistamine is identified as a high affinity, full agonist for the human H4 receptor (Lim et al., 2005). [3H]-Histamine has been used to label the H4 receptor in heterologous expression systems.

Further Reading

Akdis CA, Simons FE (2006). Histamine receptors are hot in immunopharmacology. Eur J Pharmacol533: 69–76.

de Esch I, Thurmond RL, Jongejan A, Leurs R (2005). The histamine H4 receptor as a new therapeutic target for inflammation. Trends Pharmacol Sci26: 462–469.

Esbenshade TA, Fox GB, Cowart MD (2006). Histamine H3 receptor antagonists: preclinical promise for treating obesity and cognitive disorders. Mol Interv6: 77–88.

Hancock AA (2006). The challenge of drug discovery of a GPCR target: analysis of preclinical pharmacology of histamine H3 antagonists/inverse agonists. Biochem Pharmacol71: 1103–1113.

Hill SJ, Ganellin CR, Timmerman H, Schwartz JC, Shankley NP, Young JM et al. (1997). International Union of Pharmacology. XIII. Classification of histamine receptors. Pharmacol Rev49: 253–278.

Leurs R, Bakker RA, Timmerman H, de Esch I (2005). The histamine H3 receptor: from gene cloning to H3 receptor drugs. Nat Rev Drug Discovery4: 107–120.

Lim HD, Smits RA, Leurs R, de Esch I (2006). The emerging role of the histamine H4 receptor in anti-inflammatory therapy. Curr Top Med Chem6: 1365–1373.

Tanimoto A, Sasaguri Y, Ohtsu H (2006). Histamine network in atherosclerosis. Trends Cardiovasc Med16: 280–284.

Yanai K, Tashiro M (2007). The physiological and pathophysiological roles of neuronal histamine: An insight from human positron emission tomography studies. Pharmacol Ther113: 1–15.

Zhang M, Thurmond RL, Dunford PJ (2007). The histamine H4 receptor: a novel modulator of inflammatory and immune disorders. Pharmacol Ther113: 594–606.

References

Hancock AA et al. (2004). Eur J Pharmacol487: 183–197.

Jablonowski JA et al. (2003). J Med Chem46: 3957–3960.

Kitbunnadaj R et al. (2005). Bioorg Med Chem13: 6309–6323.

Leurs R et al. (1994). Br J Pharmacol112: 847–854.

Lim HD et al. (2005). J Pharmacol Exp Ther314: 1310–1321.

Lim HD et al. (2006). J Med Chem49: 6650–6651.

Liu C et al. (2001). Mol Pharmacol59: 420–426.

Nakamura T et al. (2000). Biochem Biophys Res Commun279: 615–620.

Nguyen T et al. (2001). Mol Pharmacol59: 427–433.

Oda T et al. (2000). J Biol Chem275: 36781–36786.

Smit MJ et al. (1996). J Neurochem67: 1791–1800.

Thurmond RL et al. (2004). J Pharmacol Exp Ther309: 404–413.

Zhu Y et al. (2001). Mol Pharmacol59: 434–441.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

KISS1, Neuropeptide FF, Prolactin-releasing peptide and QRFP

Overview: KISS1, neuropeptide FF (NPFF), prolactin-releasing peptide (PrP) and QRFP receptors (provisional nomenclature) respond to endogenous peptides with an arginine-phenylalanine-amide (RFamide) motif. Kisspeptin-54 (KP54, originally named metastin), KP13 and KP10 are biologically-active peptides cleaved from the KISS1 gene product (ENSG00000170498), while a single propeptide precursor (ENSG00000139574) generates the octapeptides NPFF (FLFQPQRF-NH2, neuropeptide FF or F-8-F-amide) and NPSF (SLAAPQRF-NH2, neuropeptide SF) and the octadecapeptide NPAF (AGEGLSSPFWSLAAPQRF-NH2, neuropeptide AF or A-18-F-amide). NPFF and NPAF were originally isolated from bovine brain (Yang et al., 1985). The precursor (ENSG00000071677) for PrRP generates 31 and 20-amino-acid versions. QRFP (named after a pyroglutamylated arginine-phenylalanine-amide peptide) is a 43 amino acid peptide derived from ENSG00000188710, and is also known as P518 or 26RFa. RFRP is an RF amide-related peptide (Hinuma et al., 1998) derived from a FMRFamide-related peptide precursor (ENSG00000105954), which is cleaved to generate neuropeptide NPSF (Neuropeptide RFRP-1), neuropeptide RFRP-2 and neuropeptide NPVF (neuropeptide RFRP-3).

NomenclatureKISS1NPFF1NPFF2PrRPQRFP
Other nameshOT7T175 (Ohtaki et al., 2001), GPR54, metastin, hypogonadotropinNeuropeptide FF 1, GPR147 (Bonini et al., 2000), OT7T022Neuropeptide FF 2, GPR74 (Bonini et al., 2000), HLWAR77Prolactin-releasing peptide, GPR10 (Hinuma et al., 1998), hGR3, UHR-1SP9155 (Jiang et al., 2003), AQ27 (Fukusumi et al., 2003), P518
Ensembl IDENSG00000116014ENSG00000148734ENSG00000056291ENSG00000119973ENSG00000186867
Principal transductionGq/11 (Kotani et al., 2001; Muir et al., 2001)Gq/11Gi/o (Mollereau et al., 2005)Gq/11 (Langmead et al., 2000)Gq/11, Gi/o (Fukusumi et al., 2003)
Potency orderFMRF, NPFF > NPAF > NPSF, QRFP, PrP31 (Gouardères et al., 2007)NPAF, NPFF >PrP31 >FMRF, QRFP >NPSF (Gouardères et al., 2007)PrRP20, PrRP31 (Langmead et al., 2000)
Selective agonistsKP54, KP13, KP10 (Kotani et al 2001; Ohtaki et al., 2001)NPFFNPFFPrRPQRFP
Selective antagonistsNeuropeptide Y (Lagerstrom et al., 2005)
Probes[125I]-KP10 (Kotani et al., 2001); [125I]-KP13 (Mead et al., 2007)[125I]-NPFF, [125I]-YVP (Gouardères et al., 2002)[125I]-NPFF, [125I]-EYF (Gouardères et al., 2002)[125I]-PrRP20 (Langmead et al., 2000)[125I]-QRFP (Takayasu et al., 2006)

An orphan receptor GPR83 (ENSG00000123901) shows sequence similarities with NPFF1, NPFF2, PrRP and QRFP receptors.

Further Reading

Colledge WH (2004). GPR54 and puberty. Trends Endocrinol Metab15: 448–453.

Dhillo WS, Murphy KG, Bloom SR (2007). The neuroendocrine physiology of kisspeptin in the human. Rev Endocr Metab Disord8: 41–46.

Dungan HM, Clifton DK, Steiner RA (2006). Kisspeptin neurons as central processors in the regulation of gonadotropin-releasing hormone secretion. Endocrinology147: 1154–1158.

Fukusumi S, Fujii R, Hunuma S (2006). Recent advances in mammalian RFamide peptides: the discovery and functional analyses of PrRP, RFRPs and QRFP. Peptides27: 1073–1086.

Gottsch ML, Clifton DK, Steiner RA (2006). Kisspepeptin-GPR54 signaling in the neuroendocrine reproductive axis. Mol Cell Endocrinol254–255: 91–96.

Mead EJ, Maguire JJ, Kuc RE, Davenport AP (2007). Kisspeptins: a multifunctional peptide system with a role in reproduction, cancer and the cardiovascular system. Br J Pharmacol151: 1143–1153.

Popa SM, Clifton DK, Steiner RA (2005). A KiSS to remember. Trends Endocrinol Metabol16: 249–250.

Samson WK, Taylor MM (2006). Prolactin releasing peptide (PrRP): an endogenous regulator of cell growth. Peptides27: 1099–1103.

Seminara SB (2006). Mechanisms of Disease: the first kiss-a crucial role for kisspeptin-1 and its receptor, G-protein-coupled receptor 54, in puberty and reproduction. Nat Clin Pract Endocrinol Metab2: 328–334.

Sun B, Fujiwara K, Adachi S, Inoue K (2005). Physiological roles of prolactin-releasing peptide. Regul Rept126: 27–33.

Vyas N, Mollereau C, Cheve G, McCurdy CR (2006). Structure-activity relationships of neuropeptide FF and related peptidic and non-peptidic derivatives. Peptides27: 990–996.

References

Bonini JA et al. (2000). J Biol Chem275: 39324–39331.

Fukusumi S et al. (2003). J Biol Chem278: 46387–46395.

Gouardères C et al. (2002). Neuroscience115: 349–361.

Gouardères C et al. (2007). Neuropharmacology52: 376–386.

Hinuma S et al. (1998). Nature393: 272–276.

Jiang Y et al. (2003). J Biol Chem278: 27652–27657.

Kotani M et al. (2001). J Biol Chem276: 34631–34636.

Lagerstrom MC et al. (2005). Genomics85: 688–703.

Langmead CJ et al. (2000). Br J Pharmacol131: 683–688.

Mead EJ et al. (2007). Endocrinology148: 140–147.

Mollereau C et al. (2005). Mol Pharmacol67: 965–975.

Muir A et al. (2001). J Biol Chem276: 28969–28975.

Ohtaki T et al. (2001). Nature411: 613–617.

Takayasu S et al. (2006). Proc Natl Acad Sci USA103: 7438–7443.

Yang HY et al. (1985). Proc Natl Acad Sci USA82: 7757–7761.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Leukotriene, lipoxin, oxoeicosanoid and resolvin E1

Overview: Leukotriene receptors (nomenclature agreed by NC-IUPHAR on Leukotriene and Lipoxin Receptors, Brink et al., 2003) are activated by the endogenous ligands leukotriene (LT) B4, LTC4, LTD4, LTE4, 12R-HETE and 12S-HETE. Lipoxin A4 receptors (ALX, nomenclature agreed by NC-IUPHAR on Leukotriene and Lipoxin Receptors; Brink et al., 2003) are activated by the endogenous lipid-derived, anti-inflammatory ligands lipoxin A4 (LXA4) and 15-epi-LXA4 (aspirin-triggered lipoxin A4, ATL). Oxoeicosanoid receptors (OXE, nomenclature agreed by NC-IUPHAR on Oxoeicosanoid Receptors; Brink et al., 2004) are activated by endogenous chemotactic eicosanoid ligands oxidised at the C-5 position, with 5-oxo-ETE the most potent agonist identified for this receptor. Resolvin receptors (provisional nomenclature) are activated by the lipid-derived, anti-inflammatory ligand resolvin E1 (RvE1), which is the result of sequential metabolism of EPA by aspirin-modified cyclooxygenase and lipoxygenase (Arita et al., 2005a, b).

CysLT1 and CysLT2 are co-expressed by most myeloid cells. However, the function of CysLT2 remains unclear. CysLT2 has been demonstrated to exert a suppressive influence on CysLT1 expression, suggesting an autoregulatory function which is indicated by a reported up-regulation of CysLT-mediated responses in mice lacking CysLT2 receptors (Jiang et al., 2007).

Leukotrienes bind extensively to enzymes in their metabolic pathways (glutathione-S-transferase/LTC4 synthase, γ-glutamyltranspeptidase and several aminopeptidases) and can also bind to peroxisome proliferator-activated receptor α (PPARα, Lin et al., 1999) and the ALX lipoxin receptor (Fiore et al., 1994), complicating the interpretation of radioligand binding and functional studies (e.g. LTC4 is rapidly converted in many systems to LTD4). Metabolic inhibitors (e.g. serine-borate complex) reduce this problem but can also have nonspecific effects. The ALX receptor also interacts with endogenous peptide and protein ligands, such as MHC binding peptide (Chiang et al., 2000) as well as annexin 1 (ANXA1) and its N-terminal peptides (Perretti et al., 2002). In addition, a soluble hydrolytic product of protease action on the urokinase-type plasminogen activator receptor has been reported to activate the ALX receptor (Resnati et al., 2002). Furthermore, ALX has been suggested to act as a receptor mediating proinflammatory actions of the acute-phase reactant, serum amyloid A (Su et al., 1999; Sodin-Semrl et al., 2004).

NomenclatureBLT1BLT2CysLT1CysLT2
Other namesLTB4HG55, HMTMF81, LTD4HPN321, LTC4
Ensemble IDENSG00000116329ENSG00000082556ENSG00000112038ENSG00000125510
Principal transductionGq/11, Gi/oGq/11, Gi/oGq/11Gq/11
Rank order of potencyLTB4>20-hydroxy-LTB4 >> 12R-HETE (Yokomizo et al., 2001)LTB4 > 12S-HETE = 12S-HPETE > 15S-HETE > 12R-HETE=15S-HETE > 20-hydroxy-LTB4 (Yokomizo et al., 2001)LTD4>LTC4>LTE4 (Sarau et al., 1999)LTC4=LTD4>>LTE4 (Nothacker et al., 2000)
Selective agonists12S-HETEBAYu9773
Selective antagonistsCP105696 (pIC50 7.2), U75302 (pIC50 6.9)LY255283 (pIC50 6.0)Zafirlukast (9.5), montelukast (9.3), SR2640 (8.7), pobilukast (8.6), sulukast (8.3)
Probes[3H]-LTB4 (0.2–0.7 nM), [3H]-CGS23131 (13 nM)[3H]-LTB4 (0.2–23 nM)[3H]-LTD4, [3H]-ICI198615[3H]-LTD4

BAYu9773 is an antagonist at CysLT1 (6.8–7.7) and a reduced efficacy agonist at CysLT2 receptors. The CysLT1 and CyLT2 receptors also respond to uracil nucleotides (Mellor et al., 2001, 2003). GPR17 has been described as a ‘dualistic’ receptor responding to both uracil nucleotides and cysteinyl leukotrienes, responses which may be inhibited by antagonists of either P2 or CysLT receptors (Ciana et al., 2006).

NomenclatureALXOXERvE1
Other namesFPRL1, FPR2, FPRH2, RFPTG1019 (Hosoi et al., 2002), R527 (Jones et al., 2003), hGPCR48 (Koike et al., 2006)ChemR23, chemokine receptor-like 1, DEZ
Ensembl IDENSG00000171049ENSG00000162881ENSG00000174600
Principal transductionGi (Maddox et al., 1997)Gi/o (O'Flaherty et al., 2000; Hosoi et al., 2002; Jones et al., 2003; Hosoi et al., 2005)Not yet established
Rank order of potencyLXA4 =ATL =ATLa2>LTC4 =LTD4>> 15-deoxy-LXA4>>fMLP (Clish et al., 1999; Fiore et al., 1994; Fiore and Serhan, 1995; Gronert et al., 2001; Takano et al., 1997)5-Oxo-ETE>>5(S)-HpETE>5(S)-HETE (Hosoi et al., 2002; Jones et al., 2003)RvE1>chemerin C-terminal peptide (Arita et al., 2005a, b)
Selective agonistsLXA4, ATL, ATLa2 (Guilford et al., 2004)5-Oxo-ETE
Probes[3H]-LXA4 (0.2–1.7 nM; Fiore et al., 1994; Takano et al., 1997)[3H]-5-oxo-ETE (3.8 nM; (O'Flaherty et al., 1998)[3H]-RvE1 (48 nM; Arita et al., 2007)

A receptor selective for LXB4 has been suggested from functional studies (Maddox and Serhan, 1996; Romano et al., 1996; Ariel et al., 2003). Initial characterization of the heterologously expressed OXE receptor suggested that polyunsaturated fatty acids, such as DHA and EPA, acted as receptor antagonists (Hosoi et al., 2002).

Abbreviations: 12R-HETE, 12(R)-hydroxyeicosa-5z, 8z, 10E, 14z-tetraenoic acid; 5(S)-HETE, 5(S)-hydroxy-6E, 8z, 11z, 14z-eicosatetraenoic acid; 5(S)-HpETE, 5(s)-hydroperoxy-6E, 8z, 11z, 14z-eicosatetraenoic acid; 5-oxo-ETE, 5-oxo-6E, 8z, 11z, 14z-eicosatetraenoic acid; ANXA1, annexin 1; ATL, aspirin-triggered lipoxin A4 [15-epi-LXA4, 5S, 6R, 15R-trihydroxyl-7E, 9E, 13E, 11z-eicosatetraenoic acid]; ATLa2, ATL analog [15-epi-16-(para-fluoro)-phenoxy-LXA4]; BAYu9773, 6(R)-(4′-carboxyphenyl-thio)-5(S)-hydroxy-7E, 11z, 14z-eicosatetraenoic acid; CGS23131, (E)-5-(3-carboxybenzoyl)-2-([6-{4-methoxyphenyl}-5-hexenyl]oxy)benzene propanoic acid, also known as LY223982; CP105696, (+)-1-(3S, 4R)-[3-(4-phenylbenzyl)-4-hydroxy-chroman-7-yl]cyclopentane carboxylic acid; DHA, 4z, 7z, 10z, 13z, 16z, 19z-docosahexaenoic acid; EPA, 5z, 8z, 11z, 14z, 17z-eicosapentaenoic acid; ICI198615, (1-[2-methoxy-4-{([phenylsulfonylamino]carbonyl)phenyl}methyl]-1H-indazol-6-yl)carbamic acid cyclopentyl ester; LTC4, leukotriene C4; LTD4, leukotriene D4; LXA4, lipoxin A4 [5S, 6R, 15S-trihydroxyl-7E, 9E, 13E-11z-eicosatetraenoic acid]; LY255283, 1-[5-ethyl-2-hydroxy-4-[[6-methyl-6-(1H-tetrazol-5-yl)-heptyl]-oxy]-phenyl]-ethanone; OXE, oxoeicosanoid; RvE1, resolvin E1 or 5S, 12R, 18R-trihydroxy-6z, 8E, 10E, 14z, 16E-EPA|SR2640, 2-(3-[2-quinolylmethoxy]phenylamino)benzoic acid; U75302, 6-(6-(3-hydroxy-1E, 5z-undecadien-1-yl)-2-pyridinyl)-1, 5-hexanediol

Further Reading

Ariel A, Serhan CN (2007). Resolvins and protectins in the termination program of acute inflammation. Trends Immunol28: 176–183.

Arita M, Oh SF, Chonan T, Hong S, Elangovan S, Sun YP et al. (2006). Metabolic inactivation of resolvin E1 and stabilization of its anti-inflammatory actions. J Biol Chem281: 22847–22854.

Brink C, Dahlen SE, Drazen J, Evans JF, Hay DWP, Nicosia S et al. (2003). International Union of Pharmacology. XXXVII. Nomenclature for Leukotriene and Lipoxin Receptors. Pharmacol Rev55: 195–227.

Brink C, Dahlen SE, Drazen J, Evans JF, Hay DWP, Rovati GE et al. (2004). International Union of Pharmacology XLIV. Nomenclature for the oxoeicosanoid receptor. Pharmacol Rev56: 149–157.

Chiang N, Arita M, Serhan CN (2005). Anti-inflammatory circuitry: lipoxin, aspirin-triggered lipoxins and their receptor ALX. Prostaglandins Leukot Essent Fatty Acids73: 163–177.

Chiang N, Serhan CN, Dahlen SE, Drazen JM, Hay DW, Rovati GE et al. (2006). The lipoxin receptor ALX: potent ligand-specific and stereoselective actions in vivo. Pharmacol Rev58: 463–487.

Jones CE (2005). The OXE receptor: a new therapeutic approach for asthma? Trends Mol Med11: 266–270.

O'Flaherty JT, Rogers LC, Paumi CM, Hantgan RR, Thomas LR, Clay CE et al. (2005). 5-Oxo-ETE analogs and the proliferation of cancer cells. Biochim Biophys Acta1736: 228–236.

Peters-Golden M, Canetti C, Mancuso P, Coffey MJ (2005). Leukotrienes: underappreciated mediators of innate immune responses. J Immunol174: 589–594.

Powell WS, Rokach J (2005). Biochemistry, biology and chemistry of the 5-lipoxygenase product 5-oxo-ETE. Prog Lipid Res44: 154–183.

Rubin P, Mollison KW (2007). Pharmacotherapy of diseases mediated by 5-lipoxygenase pathway eicosanoids. Prostaglandins Other Lipid Mediat83: 188–197.

Schwab JM, Serhan CN (2006). Lipoxins and new lipid mediators in the resolution of inflammation. Curr Opin Pharmacol6: 414–420.

Serhan CN (2005). Novel ω-3-derived local mediators in anti-inflammation and resolution. Pharmacol Ther105: 7–21.

Serhan CN (2007). Resolution phases of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. Annu Rev Immunol25: 101–137.

Serhan CN, Savill J (2005). Resolution of inflammation: the beginning programs the end. Nat Immunol6: 1191–1197.

Serhan CN, Wasserman SI (2006). The allergy archives: pioneer and milestones. The discovery and characterization of the leukotrienes. J Allergy Clin Immunol118: 972–980.

References

Ariel A et al. (2003). J Immunol170: 6266–6272.

Arita M et al. (2005a). J Exp Med201: 713–722.

Arita M et al. (2005b). J Immunol178: 3912–3917.

Chiang N et al. (2000). J Exp Med191: 1197–1208.

Ciana P et al. (2006). EMBO J25: 4615–4627.

Clish CB et al. (1999). Proc Natl Acad Sci USA96: 8247–8252.

Fiore S et al. (1994). J Exp Med180: 253–260.

Fiore S, Serhan CN (1995). Biochemistry34: 16678–16686.

Gronert K et al. (2001). Am J Pathol158: 3–9.

Guilford WJ et al. (2004). J Med Chem47: 2157–2165.

Hosoi T et al. (2002). J Biol Chem277: 31459–31465.

Hosoi T et al. (2005). Biochem Biophys Res Commun334: 987–995.

Jiang Y et al. (2007). Blood110: 3263–3270.

Jones CE et al. (2003). Mol Pharmacol63: 471–477.

Koike D et al. (2006). J Biochem (Tokyo)139: 543–549.

Lin Q et al. (1999). Biochemistry38: 185–190.

Maddox JF et al. (1997). J Biol Chem272: 6972–6978.

Maddox JF, Serhan CN (1996). J Exp Med183: 137–146.

Mellor EA et al. (2001). Proc Natl Acad Sci USA98: 7964–7969.

Mellor EA et al. (2003). Proc Natl Acad Sci USA100: 11589–11593.

Nothacker HP et al. (2000). Mol Pharmacol58: 1601–1608.

O'Flaherty JT et al. (1998). J Biol Chem273: 32535–32541.

O'Flaherty JT et al. (2000). J Immunol164: 3345–3352.

Perretti M et al. (2002). Nat Med8: 1296–1302.

Resnati M et al. (2002). Proc Natl Acad Sci USA99: 1359–1364.

Romano M et al. (1996). J Immunol157: 2149–2154.

Sarau HM et al. (1999). Mol Pharmacol56: 657–663.

Sodin-Semrl S et al. (2004). Int J Immunopathol Pharmacol17: 145–156.

Su SB et al. (1999). J Exp Med189: 395–402.

Takano T et al. (1997). J Exp Med185: 1693–1704.

Yokomizo T et al. (2001). J Biol Chem276: 12454–12459.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Lysophosphatidic acid

Overview: Lysophosphatidic acid (LPA) receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Lysophospholipid Receptors; Chun et al., 2002) are activated by the endogenous lipid derivative LPA. The identified receptors can account for most, although not all, LPA-induced phenomena in the literature, indicating that a majority of LPA-dependent phenomena are receptor-mediated. Radioligand binding has been conducted in heterologous expression systems using [3H]-LPA (e.g. Fukushima et al., 1998). In native systems, analysis of binding data is complicated by metabolism and high levels of nonspecific binding, and therefore the relationship between recombinant and endogenously expressed receptors is unclear. Targeted deletion of LPA receptors has clarified signalling pathways and identified physiological and pathophysiological roles. LPA has also been described to be an agonist at PPARγ receptors (McIntyre et al., 2003), although the physiological significance of this observation remains unclear (Simon et al., 2005).

NomenclatureLPA1LPA2LPA3LPA4LPA5
Other namesVZG-1, Edg2, lpA1Edg4, lpA2Edg7, lpA3p2y9, gpr23GPR92
Ensembl IDENSG00000119438ENSG00000064547ENSG00000171517ENSG00000147149ENSG00000184574
Principal transductionGi/o, Gq/11, G12/13Gi/o, Gq/11, G12/13Gi/o, Gq/11, GsGi/o, Gq/11, Gs, G12/13 (Lee et al., 2007)Gq, G12/13 (Kotarsky et al., 2006; Lee et al., 2006)
Selective agonistsFAP10, FAP12 (Virag et al., 2003)OMPT (Hasegawa et al., 2003)
Selective antagonistsKi16425 (Ohta et al., 2003)DGPP 8:0 (Ohta et al., 2003)

FAP12 has antagonist activity at LPA1 and LPA3 receptors (Virag et al., 2003). The selectivity of these antagonists is less than two orders of magnitude. None of the currently available chemical tools have validated specificity in vivo.

Abbreviations: DGPP 8:0, dioctanoylglycerol pyrophosphate; FAP10, decanol phosphate; FAP12, dodecanol phosphate; Ki16425, 3-(4-[4-{(1-[2-chlorophenyl]ethoxy)carbonylamino}-3-methyl-5-isoxazolyl]benzylsulfanyl)propanoic acid; OMPT, 1-oleoyl-2-O-methyl-rac-glycerophos-phothionate

Further Reading

Anliker B, Chun J (2004). Lysophospholipid G protein-coupled receptors. J Biol Chem279: 20555–20558.

Chun J, Goetzl EJ, Hla T, Igarashi Y, Lynch KR, Moolenaar W et al. (2002). International union of pharmacology. XXXIV. Lysophospholipid receptor nomenclature. Pharmacol Rev54: 265–269.

Chun J, Rosen H (2006). Lysophospholipid receptors as potential drug targets in tissue transplantation and autoimmune diseases. Curr Pharm Des12: 161–171.

Gardell SE, Dubin AE, Chun J (2006). Emerging medicinal roles for lysophospholipid signaling. Trends Mol Med12: 65–75.

Goetzl EJ, Tigyi G (2004). Lysophospholipids and their G protein-coupled receptors in biology and diseases. J Cell Biochem92: 867–868.

Ishii I, Fukushima N, Ye XQ, Chun J (2004). Lysophospholipid receptors: signaling and biology. Annu Rev Biochem73: 321–354.

Kostenis E (2004). Novel clusters of receptors for sphingosine-1-phosphate, sphingosylphosphorylcholine, and (lyso)-phosphatidic acid: new receptors for ‘old’ ligands. J Cell Biochem92: 923–936.

Lin DA, Boyce JA (2006). Lysophospholipids as mediators of immunity. Adv Immunol89: 141–167.

Meyer Zu Heringdorf D, Jakobs KH (2007). Lysophospholipid receptors: signalling, pharmacology and regulation by lysophospholipid metabolism. Biochim Biophys Acta1768: 923–940.

Radeff-Huang J, Seasholtz TM, Matteo RG, Brown JH (2004). G protein mediated signaling pathways in lysophospholipid induced cell proliferation and survival. J Cell Biochem92: 949–966.

References

Fukushima N et al. (1998). Proc Natl Acad Sci USA95: 6151–6156.

Hasegawa Y et al. (2003). J Biol Chem278: 11962–11969.

Kotarsky K et al. (2006). J Pharmacol Exp Ther318: 619–628.

Lee CW et al. (2006). J Biol Chem281: 23589–23597.

Lee CW et al. (2007). J Biol Chem282: 4310–4317.

Ohta H et al. (2003). Mol Pharmacol64: 994–1005.

Simon MF et al. (2005). J Biol Chem280: 14656–14662.

Virag T et al. (2003). Mol Pharmacol63: 1032–1042.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Melanin-concentrating hormone

Overview: Melanin-concentrating hormone (MCH) receptors (provisional nomenclature) are activated by an endogenous nonadecameric cyclic peptide identical in humans and rats (DFDMLRCMLGRVYRPCWQV) generated from a precursor (ENSG00000183395), which also produces neuropeptides EI and GE. The MCH2 receptor appears to be a non-functional pseudogene in rodents (Tan et al., 2002).

NomenclatureMCH1MCH2
Other namesSLC-1, GPR24SLT, GPRv17
Ensembl IDENSG00000128285ENSG00000152034
Principal transductionGq/11, Gi/oGq/11 (Hill et al., 2001; Mori et al., 2001; Rodriguez et al., 2001)
Rank order of potencyHuman MCH> salmon MCHHuman MCH=salmon MCH (Hill et al., 2001)
Selective antagonistsSNAP7941 (9.2, Borowsky et al., 2002), T226296 (7.5, Takekawa et al., 2002)
Probes[3 H]-MCH (Burgaud et al., 1997), [Phe13, [125I]-Tyr19] MCH (Burgaud et al., 1997), [125I]-S36057 (0.04 nM, Audinot et al., 2001)

Abbreviations: S36057, 3-iodo-tyr-(8-amino-3,6-dioxyoctanoyl)MCH-(6-17); SNAP7941, (+)-methyl(4S)-3-([{3-(4-[3-{acetylamino}phenyl]-1-piperidinyl)propyl}amino]carbonyl)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate hydrochloride; T226296, (-)-N-[6-(dimethylamino)-methyl]-5,6,7,8-tetrahydro-2-naphthalenyl]-4′-fluoro[1,1′-biphenyl]-4-carboxamide

Further Reading

Handlon AL, Zhou H (2006). Melanin-concentrating hormone-1 receptor antagonists for the treatment of obesity. J Med Chem49: 4017–4022.

Pissios P, Bradley RL, Maratos-Flier E (2006). Expanding the scales: The multiple roles of MCH in regulating energy balance and other biological functions. Endocr Rev27: 606–620.

Rokosz LL, Hobbs DW (2006). Biological examination of melanin concentrating hormone receptor 1: multi-tasking from the hypothalamus. Drug News Perspect19: 273–286.

Shimazaki T, Yoshimizu T, Chaki S (2006). Melanin-concentrating hormone MCH1 receptor antagonists: a potential new approach to the treatment of depression and anxiety disorders. CNS Drugs20: 801–811.

References

Audinot V et al. (2001). Br J Pharmacol133: 371–378.

Borowsky B et al. (2002). Nat Med8: 825–830.

Burgaud JL et al. (1997). Biochem Biophys Res Commun241: 622–629.

Hill J et al. (2001). J Biol Chem276: 20125–20129.

Mori M et al. (2001). Biochem Biophys Res Commun283: 1013–1018.

Rodriguez M et al. (2001). Mol Pharmacol60: 632–639.

Takekawa S et al. (2002). Eur J Pharmacol438: 129–135.

Tan CP et al. (2002). Genomics79: 785–792.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Melanocortin

Overview: Melanocortin receptors (provisional nomenclature) are activated by members of the melanocortin family (MSH—α, β, and γ forms— δ form is not found in mammals) and adrenocorticotrophin (ACTH). Endogenous antagonists include agouti and agouti-related protein (AGRP).

NomenclatureMC1MC2MC3MC4MC5
Other namesACTH receptor
Ensembl IDENSG00000141037ENSG00000185231ENSG00000124089ENSG00000166603ENSG00000176136
Principal transductionGsGsGsGsGs
Rank order of potencyα-MSH > β-MSH ≥ ACTH, γ-MSHACTHγ-MSH, β-MSH ≥ ACTH, α-MSHβ-MSH ≥ α-MSH, ACTH > γ-MSHα-MSH ≥ β-MSH ≥ ACTH > γ-MSH
Selective agonistsD-Trp8-γ-MSH (Grieco et al., 2000)THIQ (Van der Ploeg et al., 2002)
Selective antagonistsHS014 (8.5, Schiöth et al., 1998), MBP10 (Bednarek et al., 2001)
Probes[125I]-NDP-MSH[125I]-ACTH-(1–24)[125I]-NDP-MSH, [125I]-SHU9119[125I]-NDP-MSH, [125I]-SHU9119[125I]-NDP-MSH

Polymorphisms of the MC1 receptor have been linked to variations in skin pigmentation. Defects of the MC2 receptor underlie familial glucocorticoid deficiency. Polymorphisms of the MC4 receptor have been linked to obesity (Chagnon et al., 1997).

Abbreviations: HS014, cyc(S–S)-(Ac-Cys11,D-Nal14,Cys18,Asp-NH2)β-MSH-(11–22); MBP10, cyclo(6β→10ɛ)(succinyl(6)-D-(2′)Nal7-Arg8-Trp9-Lys10)-NH2; NDP-MSH, [Nle4,d-Phe7]α-MSH; SHU9119, Ac-Nle-Asp-His-d-Nal2-Arg-Trp-Lys-NH2; THIQ, N-([3R]-1,2,3,4-tetrahydroisoquinolinium-3-ylcarbonyl)-(1R)-1-(4-chlorobenzyl)-2-(4-cyclohexyl-4-[1H-1,2,4-triazol-1ylmethyl]piperidin-1-yl)-2-oxoethylamine

Further Reading

Cone RD (2006). Studies on the physiological functions of the melanocortin system. Endocr Rev27: 736–749.

DeBoer MD, Marks DL (2006). Cachexia: lessons from melanocortin antagonism. Trends Endocrinol Metab17: 199–204.

DeBoer MD, Marks DL (2006). Therapy insight: use of melanocortin antagonists in the treatment of cachexia in chronic disease. Nat Clin Pract Endocrinol Metab2: 459–466.

Getting SJ (2006). Targeting melanocortin receptors as potential novel therapeutics. Pharmacol Ther111: 1–15.

Nargund RP, Strack AM, Fong TM (2006). Melanocortin-4 receptor (MC4R) agonists for the treatment of obesity. J Med Chem49: 4035–4043.

Ramos EJ, Meguid MM, Campos AC, Coelho JC (2005). Neuropeptide Y, α-melanocyte-stimulating hormone, and monoamines in food intake regulation. Nutrition21: 269–279.

Williams DL, Schwartz MW (2005). The melanocortin system as a central integrator of direct and indirect controls of food intake. Am J PhysiolRegul Integr Comp Physiol289: R2–R3.

References

Bednarek MA et al. (2001). J Med Chem44: 3665–3672.

Chagnon YC et al. (1997). Mol Med3: 663–673.

Grieco P et al. (2000). J Med Chem43: 4998–5002.

Schiöth HB et al. (1998). Br J Pharmacol124: 75–82.

Van Der Ploeg LH et al. (2002). Proc Natl Acad Sci USA99: 11381–11386.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Melatonin

Overview: Melatonin receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on melatonin receptors (see Dubocovich et al., 1998, 2000) are activated by the endogenous ligands melatonin and N-acetylserotonin.

NomenclatureMT1MT2MT3
Other namesMEL1A, ML1A, Mel1aMEL1B, ML1B, Mel1bML2
Ensembl IDENSG00000168412ENSG00000134640
Principal transductionGi/oGi/o
Selective agonistsIIK7 Sugden et al. (1999), 5-methoxyluzindole Dubocovich et al. (1998)N-acetylserotonin (Eison and Mullins (1993); Popova and Dubocovich (1995); Molinari et al. (1996); Lucchelli et al. (1997), 5MCA-NAT Popova and Dubocovich (1995)
Selective antagonistsK185 (9.3, Sugden et al., 1999), 4P-PDOT (8.8, Dubocovich et al. (1997); Dubocovich et al., 1998), DH97 (8.0, Teh and Sugden, 1998)Prazosin Lucchelli et al. (1997)
Probes[3H]-melatonin Browning et al. (2000)[3H]-melatonin Browning et al. (2000)2-iodo-[125I]-5MCA-NAT Molinari et al. (1996)

Melatonin, 2-iodo-melatonin, S20098, GR196429, LY156735 and TAK375 (Kato et al., 2005) are nonselective agonists for MT1 and MT2 receptors. 2-Iodo-[125I]-melatonin can be used to label all three melatonin receptor subtypes. (-)-AMMTC displays an ∼ 400-fold greater agonist potency than (+)-AMMTC at rat MT1 receptors (Ting et al., 1999). Luzindole is a non-selective melatonin receptor antagonist with some selectivity for the MT2 receptor (Dubocovich et al., 1998). The MT3 binding site of hamster kidney was identified as the hamster homologue of human quinone reductase 2 (ENSG00000124588, Nosjean et al, 2000; Nosjean et al, 2001). Pharmacological investigations of MT3 binding sites have primarily been conducted in hamster and guinea-pig tissues. A suggested physiological function of the MT3 receptor is in the control of intraocular pressure in rabbits (Pintor et al., 2003). Xenopus melanophores and chick brain express a distinct receptor (x 420, P49219; c346, P49288, initially termed Mel1C) coupled to the Gi/o family of G proteins, for which a mammalian counterpart has not yet been defined. MT1/MT2 heterodimers present different pharmacological profiles from MT1 and MT2 receptors (Ayoub et al., 2004).

Abbreviations: 4P-PDOT, 4-phenyl-2-propionamidotetraline; AMMTC, N-acetyl-4-aminomethyl-6-methoxy-9-methyl-1,2,3,4-tetrahydro-carbazole;DH97, 2-benzyl-N-pentanoyltryptamine; GR196429, N-(2-[2,3,7,8-tetrahydro-1H-furo(2,3-g)indol-1-yl]ethyl)acetamide; IIK7, N-buta-noyl-2-(2-methoxy-6H-isoindolo [2,1-a]indol-11-yl)ethanamine; K185, N-butanoyl-2-(5,6,7-trihydro-11-methoxybenzo[3,4]cyclohept[2,1-a]indol-13-yl)ethanamine; LY156735, β-methyl-6-chloromelatonin; 5MCA-NAT, 5-methoxy-carbonylamino-N-acetyltryptamine; S20098, N-(2-[7-methoxy-1-naphthalenyl]ethyl)acetamide; TAK375, (S)-N-[2(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide

Further Reading

Alarma-Estrany P, Pintor J (2007). Melatonin receptors in the eye: location, second messengers and role in ocular physiology. Pharmacol Ther113: 507–522.

Anisimov VN, Popovich IG, Zabezhinski MA, Anisimov SV, Vesnushkin GM, Vinogradova IA (2006). Melatonin as antioxidant, geroprotector and anticarcinogen. Biochim Biophys Acta1757: 573–589.

De Leersnyder H (2006). Inverted rhythm of melatonin secretion in Smith-Magenis syndrome: from symptoms to treatment. Trends Endocrinol Metab17: 291–298.

Di Bella L, Gualano L (2006). Key aspects of melatonin physiology: thirty years of research. Neuro Endocrinol Lett27: 425–432.

Dubocovich ML, Cardinali DP, Guardiola-Lemaitre B, Hagan RM, Krause DN, Sugden D et al. (1998). Melatonin receptors. In: Girdlestone D, IUPHAR (eds). The IUPHAR Compendium of Receptor Characterization and Classification. IUPHAR Media: London, pp 187–193.

Dubocovich ML, Cardinali DP, Delagrange PRM, Krause DN, Strosberg D, Sugden D et al. (2000). Melatonin Receptors. In: Girdlestone D, IUPHAR (eds). The IUPHAR Compendium of Receptor Characterization and Classification. IUPHAR Media: London, 2nd edn. pp 270–277.

Dubocovich ML, Rivera-Bermudez MA, Gerdin MJ, Masana MI (2003). Molecular pharmacology, regulation and function of mammalian melatonin receptors. Frontiers in Bioscience8: d1093–d1108.

Falcon J, Besseau L, Sauzet S, Boeuf G (2007). Melatonin effects on the hypothalamo-pituitary axis in fish. Trends Endocrinol Metab18: 81–88.

Leon J, Acuna-Castroviejo D, Sainz RM, Mayo JC, Tan DX, Reiter RJ (2004). Melatonin and mitochondrial function. Life Sci75: 765–790.

Pandi-Perumal SR, Srinivasan V, Maestroni GJ, Cardinali DP, Poeggeler B, Hardeland R (2006). Melatonin: Nature's most versatile biological signal? FEBS J273: 2813–2838.

Witt-Enderby PA, Bennett J, Jarzynka MJ, Firestine S, Melan MA (2003). Melatonin receptors and their regulation: biochemical and structural mechanisms. Life Sci72: 2183–2198.

References

Ayoub MA et al. (2004). Mol Pharmacol66: 312–321.

Browning C et al. (2000). Br J Pharmacol129: 877–886.

Dubocovich ML et al. (1997). Naunyn-Schmiedeberg's Arch Pharmacol355: 365–375.

Dubocovich ML et al. (1998). FASEB J12: 1211–1220.

Eison AS, Mullins UL (1993). Life Sci53: L393–L398.

Kato K et al. (2005). Neuropharmacology48: 301–310.

Lucchelli A et al. (1997). Br J Pharmacol121: 1775–1781.

Molinari EJ et al. (1996). Eur J Pharmacol301: 159–168.

Nosjean O et al. (2000). J Biol Chem275: 31311–31317.

Nosjean O et al. (2001). Biochem Pharmacol61: 1369–1379.

Pintor J et al. (2003). Br J Pharmacol138: 831–836.

Popova JS, Dubocovich ML (1995). J Neurochem64: 130–138.

Sugden D et al. (1999). Reprod Nutr Dev39: 335–344.

Teh MT, Sugden D (1998). Naunyn-Schmiedeberg's Arch Pharmacol358: 522–528.

Ting KN et al. (1999). Br J Pharmacol127: 987–995.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Motilin

Overview: Motilin receptors (provisional nomenclature) are activated by a 22 amino-acid peptide derived from a precursor (ENSG00000096395), which also generates motilin-associated peptide. These receptors are suggested to be responsible for the gastrointestinal prokinetic effects of motilides (particular macrolide antibiotics, see Abu-Gharbieh et al., 2004; Inui et al., 2004, Xu et al., 2005).

NomenclatureMotilin
Other namesMTLR1 (Feighner et al., 1999), GPR38 (Mckee et al., 1997)
Ensembl IDENSG00000102539
Principal transductionGq/11 (Depoortere and Peeters, 1995; Feighner et al., 1999)
Rank order of potencyMotilin> ABT229, mitemcimal > erythromycin (Clark et al., 1999)
Selective agonistsABT229 (Lartey et al., 1995), mitemcinal (Koga et al., 1994; Takanashi et al., 2007)
Selective antagonistsGM109 (Takanashi et al., 1995; pA2 7.2–7.5 Clark et al., 1999)
Probes[125I]-motilin (0.1 nM, Feighner et al., 1999)

Abbreviations: ABT229, 8,9-anhydro-4”-deoxy-3′-N-desmethyl-3′-N-ethylerythromycin B 6,9-hemiacetal; GM109, phe-cyclo[Lys-Tyr(3-tBu)-β-Ala].trifluoroacetate; mitemcinal, de(N-methyl)-11-deoxy-N-isopropyl-12-O-methyl-11-oxo-8,9-anhydroerythromycin A 6,9-hemiacetal fumaric acid, also known as GM611

Further Reading

Abu-Gharbieh E, Vasina V, Poluzzi E, de Ponti F (2004). Antibacterial macrolides: a drug class with a complex pharmacological profile. Pharmacol Res50: 211–222.

Inui A, Asakawa A, Bowers CY, Mantovani G, Laviano A, Meguid MM et al. (2004). Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ. FASEB J18: 439–456.

Takeshita E, Matsuura B, Dong M, Miller LJ, Matsui H, Onji M (2006). Molecular characterization and distribution of motilin family receptors in the human gastrointestinal tract. J Gastroenterol41: 223–230.

Xu L, Depoortere I, Vertongen P, Waelbroeck M, Robberecht P, Peeters TL (2005). Motilin and erythromycin-A share a common binding site in the third transmembrane segment of the motilin receptor. Biochem Pharmacol70: 879–887.

References

Clark MJ et al. (1999). Clin Exp Pharmacol Physiol26: 242–245.

Depoortere I, Peeters TL (1995). Regul Pept55: 227–235.

Feighner SD et al. (1999). Science284: 2184–2188.

Koga H et al. (1994). Bioorg Med Chem Lett4: 1347–1352.

Lartey PA et al. (1995). J Med Chem38: 1793–1798.

McKee KK et al. (1997). Genomics46: 426–434.

Takanashi H et al. (1995). J Pharmacol Exp Ther273: 624–628.

Takanashi H et al. (2007). Pharmacology79: 137–148.

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Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Neuromedin U

Overview: Neuromedin U receptors (provisional nomenclature) are activated by the endogenous 25 amino-acid peptide neuromedin U (NMU), with an indeterminate protein distribution, although mRNA levels indicate a predominant distribution of NMU1 receptors in the periphery, particularly the gastrointestinal tract, while NMU2 receptors appear expressed predominantly in localised regions of the CNS. NMU was originally isolated from pig spinal cord (Minamino et al., 1985). In humans, NMU appears to be the sole product of a precursor (ENSG00000109255) showing a broad tissue distribution, but which is expressed at highest levels in the upper gastrointestinal tract, CNS, bone marrow and fetal liver. Shorter versions of NMU are found in some species, being derived at least in some instances from the proteolytic cleavage of the longer NMU. Despite species differences in NMU structure, the C-terminal region (particularly the C-terminal pentapeptide) is highly conserved and contains biological activity. Neuromedin S (NMS), an endgenous 36 amino-acid peptide (ENSG00000204640), which contains an amidated C-terminal heptapeptide identical to NMU, appears to activate NMU receptors with equivalent potency (Mori et al., 2005).

NomenclatureNMU1NMU2
Other namesGPR66, FM3 (Hedrick et al., 2000; Kojima et al., 2000; Szekeres et al., 2000)FM4 (Howard et al., 2000), TGR1 (Hosoya et al., 2000)
Ensembl IDENSG00000171596ENSG00000132911
Principal transductionGq/11 (Hedrick et al., 2000)Gq/11 (Hosoya et al., 2000)
Probes[125I]-NMU-25, Cy3B-tagged NMU-8 (Brighton et al., 2004a)

Although NMU1 and NMU2 receptors couple predominantly to Gq/11, there is evidence of coupling to Gi/o (see Hosoya et al., 2000; Brighton et al., 2004b).

Abbreviations: NMS, neuromedin S; NMU, neuromedin U

Further Reading

Brighton PJ, Szekeres PG, Willars GB (2004b). Neuromedin U and its receptors: structure, function, and physiological roles. Pharmacol Rev56: 231–248.

Maguire JJ, Davenport AP (2005). Regulation of vascular reactivity by established and emerging GPCRs. Trends Pharmacol Sci26: 448–454.

References

Brighton PJ et al. (2004a). Mol Pharmacol66: 1544–1556.

Hedrick JA et al. (2000). Mol Pharmacol58: 870–875.

Hosoya M et al. (2000). J Biol Chem275: 29528–29532.

Howard AD et al. (2000). Nature406: 70–74.

Kojima M et al. (2000). Biochem Biophys Res Commun276: 435–438.

Minamino N et al. (1985). Biochem Biophys Res Commun130: 1078–1085.

Mori K et al. (2005). EMBO J24: 325–335.

Szekeres PG et al. (2000). J Biol Chem275: 20247–20250.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1-S209.

Neuropeptide S

Overview: The neuropeptide S receptor (NPS, provisional nomenclature) responds to the 20 amino-acid peptide neuropeptide S derived from a precursor (ENSG00000205730). The NPS receptor was initially identified as a G protein-coupled receptor for asthma susceptibility (GPRA, Laitinen et al., 2004).

NomenclatureNPS
Other namesGPRA (Laitinen et al., 2004), GPR154, vasopressin receptor-related receptor 1, PGR14
Ensembl IDENSG00000187258
Principal transductionGs, Gq/11 (Gupte et al., 2004; Vendelin et al., 2005)
Selective agonistsNPS
Probes[125I-Tyr10]-NPS

Polymorphisms in the NPS receptor have been suggested to be associated with asthma (Laitinen et al., 2004; Vendelin et al., 2005) and irritable bowel syndrome (D'Amato et al., 2007).

Abbreviation: NPS, neuropeptide S

Further Reading

Koob GF, Greenwell TN (2004). Neuropeptide S: a novel activating anxiolytic? Neuron43: 441–442.

Okamura N, Reinscheid RK (2007). Neuropeptide S: a novel modulator of stress and arousal. Stress10: 221–226.

Reinscheid RK, Xu YL, Civelli O (2005). Neuropeptide S: a new player in the modulation of arousal and anxiety. Mol Interv5: 42–46.

Xu YL, Reinscheid RK, Huitron-Resendiz S, Clark SD, Wang Z, Lin SH et al. (2004). Neuropeptide S: a neuropeptide promoting arousal and anxiolytic-like effects. Neuron43: 487–497.

References

D'Amato M et al. (2007). Gastroenterology133: 808–817.

Gupte J et al. (2004). Proc Natl Acad Sci USA101: 1508–1513.

Laitinen T et al. (2004). Science304: 300–304.

Vendelin J et al. (2005). Am J Respir Cell Mol Biol33: 262–270.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1-S209.

Neuropeptide Y

Overview: Neuropeptide Y (NPY) receptors (nomenclature agreed by NC-IUPHAR on Neuropeptide Y Receptors, see Michel et al., 1998) are activated by the endogenous peptides NPY, NPY-(3–36), peptide YY (PYY), PYY-(3–36) and pancreatic polypeptide (PP). The receptor originally identified as the Y3 receptor has been identified as the CXCR4 chemokine recepter (originally named LESTR, Loetscher et al., 1994). The y6 receptor is a functional gene product in mouse, absent in rat, but contains a frame-shift mutation in primates producing a truncated nonfunctional gene (Gregor et al., 1996). Many of the agonists exhibit differing degrees of selectivity dependent on the species examined. For example, the relative potency of PP is greater at the rat Y4 receptor than at the human receptor (Eriksson et al., 1998). In addition, many agonists lack selectivity for individual subtypes, but can exhibit comparable potency against pairs of NPY receptor subtypes, or have not been examined for activity at all subtypes. [125I]-PYY or [125I]-NPY can be used to label Y1, Y2, Y5 and y6 subtypes non-selectively, while [125I]-[cPP(1–7),NPY(19–23),Ala31,Aib32,Gln34]hPP may be used to label Y5 receptors preferentially.

NomenclatureY1Y2Y4Y5y6
Other namesPP1Y5, PP2, Y2B
Ensembl IDENSG00000164128ENSG00000185149ENSG00000169556ENSG00000164129ENSG00000159279
Principal transductionGi/oGi/oGi/oGi/oGi/o
Rank order of potencyNPY ≥ PYY > > PPNPY ≥ PYY > > PPPP > NPY = PYYNPY ≥ PYY ≥ PPNPY = PYY > PP
Selective agonists[Leu31,Pro34]NPY, [Pro34]NPY, [Leu31,Pro34]PYY, [Pro34]PYYNPY-(3–36), PYY-(3–36)PP[Ala31,Aib32]NPY (Cabrele et al., 2000)
Selective antagonistsBIBO3304 (9.5, Wieland et al., 1998), BIBP3226 (8.2, Gerald et al., 1996)BIIE0246 (8.5, Doods et al., 1999), JNJ5207787 (Bonaventure et al., 2004)L152804 (7.6, Kanatani et al., 2000)
Probes[125I]-[Leu31,Pro34] NPY, [3H]-BIBP3226 (2.1 nM)[125I]-PYY-(3–36)[125I]-PP[125I]-[cPP(1–7),NPY(19–23),Ala31,Aib32,Gln34]hPP (Dumont et al., 2004)

The Y1 agonists indicated are selective relative to Y2 receptors. BIBP3226 is selective relative to Y2, Y4 and Y5 receptors (Gerald et al., 1996). NPY-(13–36) is Y2 selective relative to Y1 and Y5 receptors. PYY-(3–36) is Y2 selective relative to Y1 receptors.

Abbreviations: BIBO3304, (R)-N-([4-{aminocarbonylaminomethyl}-phenyl]methyl)-N2-(diphenylacetyl)-argininamide trifluoroacetate; BIBP3226, R-N2-(diphenylacetyl)-N-(4-hydroxyphenyl)methyl-argininamide; BIIE0246, (S)-N2-([1-{2-(4-[(R,S)-5,11-dihydro-6(6H)-oxodibenz[b,e]azepin-11-yl]-1-piperazinyl)-2-oxoethyl}cyclopentyl]acetyl)-N-(2-[1,2-dihydro-3,5(4H)-dioxo-1,2-diphenyl-3H-1,2, 4-triazol-4-yl]ethyl)-argininamide; JNJ5207787,N-(1-acetyl-2,3-dihydro-1H-indol-6-yl)-3-(3-cyano-phenyl)-N-[1-(2-cyclopentylethyl)piperidin-4-yl]acrylamide; L152804, 2-(3,3-dimethyl-1-oxo-4H-1H-xanthen-9-yl)-5,5-dimethyl-cyclohexane-1,3-dione

Further Reading

Larhammar D, Salaneck E (2004). Molecular evolution of NPY receptor subtypes. Neuropeptides38: 141–151.

Michel MC (2004). Neuropeptide Y and related peptides. Handb Exp Pharmacol162: 1–555.

Michel MC, Beck-Sickinger A, Cox H, Doods HN, Herzog H, Larhammar D, Quirion R, Schwartz T, Westfall T (1998). International Union of Pharmacology XVI. Recommendations for the nomenclature of neuropeptide Y, peptide YY, and pancreatic polypeptide receptors. Pharmacol Rev50: 143–150.

Nygaard R, Nielbo S, Schwartz TW, Poulsen FM (2006). The PP-fold solution structure of human polypeptide YY and human PYY3-36 as determined by NMR. Biochemistry45: 8350–8357.

Parker E, Van Heek M, Stamford A (2002). Neuropeptide Y receptors as targets for anti-obesity drug development: perspective and current status. Eur J Pharmacol440: 173–187.

Pedrazzini T (2004). Importance of NPY Y1 receptor-mediated pathways: assessment using NPY Y1 receptor knockouts. Neuropeptides38: 267–275.

Tough IR, Holliday ND, Cox HM (2006). Y4 receptors mediate the inhibitory responses of pancreatic polypeptide in human and mouse colon mucosa. J Pharmacol Exp Ther319: 20–30.

References

Bonaventure P et al. (2004). J Pharmacol Exp Ther308: 1130–1137.

Cabrele C et al. (2000). J Biol Chem275: 36043–36048.

Doods H et al. (1999). Eur J Pharmacol384: R3-R5.

Dumont Y et al. (2004). Neuropeptides38: 163–174.

Eriksson H et al. (1998). Regul Pept75–76: 29–37.

Gerald C et al. (1996). Nature382: 168–171.

Gregor P et al. (1996). J Biol Chem271: 27776–27781.

Kanatani A et al. (2000). Biochem Biophys Res Commun272: 169–173.

Wieland HA et al. (1998). Br J Pharmacol125: 549–555.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1-S209.

Neuropeptides B and W

Overview: The neuropeptide BW receptor 1 (NPBW1, provisional nomenclature) is activated by two 23-amino-acid peptides, neuropeptide W (NPW-23) and neuropeptide B (NPB-23) (Fujii et al., 2002; Shimomura et al., 2002). C-terminally extended forms of the peptides (NPW-30 and NPB-29) also activate NPBW1 (Brezillon et al., 2003). Unique to both forms of NPB is the N-terminal bromination of the first tryptophan residue. des-Br-NPB-23 and des-Br-NPB-29 were not found to be major components of bovine hypothalamic tissue extracts. The NPBW2 receptor is activated by the short and C-terminal extended forms of NPB and NPW (Brezillon et al., 2003).

NomenclatureNPBW1NPBW2
Other namesGPR7GPR8
Ensembl IDENSG00000183729ENSG00000125522
Principal transductionGi/o (Mazzocchi et al., 2005)Gi/o (Mazzocchi et al., 2005)
Rank order of potencyNPB-29>NPB-23>NPW-23>NPW-30 (Brezillon et al., 2003)NPW-23>NPW-30>NPB-29>NPB-23 (Brezillon et al., 2003)
Selective agonistsAva-3, Ava-5 (Kanesaka et al., 2007)
Probes[125I]-NPW-23 (0.44 nM, Singh et al., 2004)[125I]-NPW-23

Potency measurements were conducted with heterologously-expressed receptors with a range of 0.14–0.57 nM (NPBW1) and 0.98–21 nM (NPBW2).

Abbreviations: Ava3, TrpTyrLysAvaAvaAvaGlyArgAlaAlaGlyLeuLeuSerGlyLeu-NH2; Ava5, TrpTyrLysAvaAvaAvaAvaAvaAvaGlyArgAlaAlaGly-LeuLeuSerGlyLeu-NH2, respectively

Further Reading

Lee DK, George SR, O'Dowd BF (2003). Continued discovery of ligands for G protein-coupled receptors. Life Sci74: 293–297.

Singh G, Davenport AP (2006). Neuropeptide B and W: neurotransmitters in an emerging G-protein-coupled receptor system. Br J Pharmacol148: 1033–1041.

References

Brezillon S et al. (2003). J Biol Chem278: 776–783.

Fujii R et al. (2002). J Biol Chem277: 34010–34016.

Kanesaka M et al. (2007). J Peptide Sci13: 379–385.

Mazzocchi G et al. (2005). J Clin Endocrinol Metab90: 3466–3471.

Shimomura Y et al. (2002). J Biol Chem277: 35826–35832.

Singh G, Davenport AP (2006). Br J Pharmacol148: 1033–1041.

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We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1-S209.

Neurotensin

Overview: Neurotensin receptors (provisional nomenclature) are activated by the endogenous tridecapeptide neurotensin (pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu) derived from a precursor (ENSG00000133636), which also generates neuromedin N, an agonist at the NTS2 receptor. A nonpeptide antagonist, SR142948A, shows high affinity (pKi∼9) at both NTS1 and NTS2 receptors (Gully et al., 1997). [3H]-Neurotensin and [125I]-neurotensin may be used to label NTS1 and NTS2 receptors at 0.1–0.3 and 3–5 nM concentrations, respectively.

NomenclatureNTS1NTS2
Other namesHigh-affinity neurotensin receptor, NTRH, NTR-1, NT1Low-affinity neurotensin receptor, NTRL, NTR-1, NT2
Ensembl IDENSG00000101188ENSG00000169006
Principal transductionGq/11Gq/11
Rank order of potencyNeurotensin>neuromedin N (Hermans et al., 1997)Neurotensin = neuromedin N (Mazella et al., 1996)
Selective agonistsJMV449 (Souaze et al., 1997)Levocobastine (Mazella et al., 1996)
Selective antagonistsSR48692 (7.5–8.2; Gully et al., 1997)
Probes[3H]-SR48692 (3.4 nM; Labbe-Jullie et al., 1995)

Neurotensin appears to be a low-efficacy agonist at the NTS2 receptor (Vita et al., 1998). An additional protein, provisionally termed NTS3 (also known as NTR3, gp95 and sortilin; ENSG00000134243), has been suggested to bind lipoprotein lipase and mediate its degradation (Nielsen et al., 1999). It has been reported to interact with the NTS1 receptor (Martin et al., 2002) and has been implicated in hormone trafficking and/or neurotensin uptake.

Abbreviations: JMV449,H-Lysψ (CH2NH)-Lys-Pro-Tyr-Ile-Leu; SR142948A, 2-([5-{2,6-dimethoxyphenyl}-1-{4-(N-[3-dimethylaminopropyl]-N-methylcarbamoyl)-2-isopropylphenyl}-1H-pyrazole-3-carbonyl]amino)adamantane-2-carboxylic acid hydrochloride; SR48692, 2-([1-{7-chloro-4-quinolinyl}-5-{2,6-dimethoxyphenyl}pyrazol-3-yl]carboxylamino)tricyclo(3.3.1.1.[3.7])decan-2-carboxylic acid

Further Reading

Boules M, Shaw A, Fredrickson P, Richelson E (2007). Neurotensin agonists: potential in the treatment of schizophrenia. CNS Drugs21: 13–23.

Dobner PR (2005). Multitasking with neurotensin in the central nervous system. Cell Mol Life Sci62: 1946–1963.

Kinkead B, Nemeroff CB (2004). Neurotensin, schizophrenia, and antipsychotic drug action. Int Rev Neurobiol59: 327–349.

References

Mazella J, Vincent JP (2006). Internalization and recycling properties of neurotensin receptors. Peptides27: 2488–2492.

Gully D et al. (1997). J Pharmacol Exp Ther280: 802–812.

Hermans E et al. (1997). Br J Pharmacol121: 1817–1823.

Labbe-Jullie C et al. (1995). Mol Pharmacol47: 1050–1056.

Martin S et al. (2002). Gastroenterology123: 1135–1143.

Mazella J et al. (1996). J Neurosci16: 5613–5620.

Nielsen MS et al. (1999). J Biol Chem274: 8832–8836.

Souaze F et al. (1997). J Biol Chem272: 10087–10094.

Vita N et al. (1998). Eur J Pharmacol360: 265–272.

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Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1-S209.

Nicotinic acid

Overview: Nicotinic acid receptors (provisional nomenclature) respond to the lipid lowering agents nicotinic acid (niacin), acipimox and acifran (Soga et al., 2003; Tunaru et al., 2003; Wise et al., 2003). Although GPR109A and GPR109B are over 95% homologous at the protein level, the former is activated by submicromolar concentrations of nicotinic acid, while the latter is only activated at millimolar concentrations (Wise et al., 2003).

NomenclatureGPR109AGPR109B
Other namesHigh affinity, HM74A, Nic1, Puma-GLow affinity, HM74, Nic2
Ensembl IDENSG00000182782ENSG00000182442
Principal transductionGi/o (Soga et al., 2003; Wise et al., 2003; Tunaru et al., 2003)Gi/o (Soga et al., 2003; Wise et al., 2003)
Selective agonistsNicotinic acid (Soga et al., 2003; Wise et al., 2003; Tunaru et al., 2003), acipimox, 3-hydroxybutyrate (Taggart et al., 2005)IBC293 (Semple et al., 2006)
Probes[3H]-Nicotinic acid (Soga et al., 2003)

GPR109A and GPR109B belong to a family of 7TM receptors (ENSF00000004244), which also includes the 5-oxoeicosanoic acid receptor and GPR31 and GPR81. Although the latter is the most closely related receptor to GPR109A and GPR109B, it fails to respond to nicotinic acid (Tunaru et al., 2003).

Abbreviations: IBC293, 1-(1-methylethyl)-1H-benzotriazole-5-carboxylic acid

Further Reading

Gille A, Bodor ET, Ahmed K, Offermanns S (2008). Nicotinic acid: pharmacological effects and mechanisms of action. Annu Rev Pharmacol Toxicol, in press.

Guyton JR (2007). Niacin in cardiovascular prevention: mechanisms, efficacy, and safety. Curr Opin Lipidol18: 415–420.

Karpe F, Frayn KN (2004). The nicotinic acid receptor-a new mechanism for an old drug. Lancet363: 1892–1894.

Offermanns S (2006). The nicotinic acid receptor GPR109A (HM74A or PUMA-G) as a new therapeutic target. Trends Pharmacol Sci27: 384–390.

Soudijn W, van Wijngaarden I, IJzerman AP (2007). Nicotinic acid receptor subtypes and their ligands. Med Res Rev27: 417–433.

References

Semple G et al. (2006). J Med Chem49: 1227–1230.

Soga T et al. (2003). Biochem Biophys Res Commun303: 364–369.

Taggart AK et al. (2005). J Biol Chem280: 26649–26652.

Tunaru S et al. (2003). Nat Med9: 352–355.

Wise A et al. (2003). J Biol Chem278: 9869–9874.

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We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1-S209.

Opioid and opioid-like

Overview: Opioid and opioid-like receptors are activated by the endogenous peptides [Met]enkephalin (met), [Leu]enkephalin (leu), β-endorphin (β-end), α-neo-dynorphin, dynorphin A (dynA), dynorphin B (dynB), Big dynorphin (Big dyn), nociceptin/orphanin FQ (N/OFQ), and endomorphin-1 and −2, although several other opioid-like peptides are found in the CNS. The Greek letter names for the opioid receptors, μ, κ, and δ, are well established and, despite digressions into other nomenclatures (see Dhawan et al., 1996), IUPHAR considers these original names most appropriate (Foord et al., 2005). The human N/OFQ receptor is considered ‘opioid-related’ rather than opioid because while it exhibits a high degree of structural homology with the conventional opioid receptors (Mollereau et al., 1994), it displays a distinct pharmacology.

NomenclatureDelta opioid receptorKappa opioid receptorMu opioid receptorN/OFQ receptor
Preferred abbreviationδκμNOP
Other namesOP1, DOP, DOROP2, KOP, KOROP3, MOP, MORORL1, OP4
Ensembl IDENSG00000116329ENSG00000082556ENSG00000112038ENSG00000125510
Principal transductionGi/oGi/oGi/oGi/o
Rank order of potencyβ-End=leu=met>dynABig dyn>dynA≥β-end>leu>metβ-End>dynA>met=leuN/OFQ≥dynA
Selective agonistsDPDPE (Mosberg et al., 1983), DSBULET (Delay-Goyet et al., 1988), [DAla2]deltorphin I or II (Erspamer et al., 1989), SNC80 (Bilsky et al., 1995)U69593 (Lahti et al., 1985), CI977 (Hunter et al., 1990), Salvinorin A (Roth et al., 2002)Endomorphin-1 and −2 (Zadina et al., 1997), morphine (Goldstein and Naidu, 1989), DAMGO (Handa et al., 1981), sufentanil (Yeadon and Kitchen, 1988), PL017 (Costa et al., 1992)N/OFQ, N/OFQ-(1–13)-NH2 (Guerrini et al., 1997), Ro646198 (Jenck et al., 2000), UFP-112 (Rizzi et al., 2007)
Selective antagonistsNaltrindole (Portoghese et al., 1988), naltriben (Sofuoglu et al., 1991)Nor-binaltorphimine (Portoghese et al., 1987), GNTI (Stevens et al., 2000)CTAP (Pelton et al., 1986),J113397 (8.3, Kawamoto et al., 1999), SB612111 (8.5, Zaratin et al., 2004), UFP101 (7.2, Calo et al., 2002)
Probes[3H]-DPDPE (Goldstein and Naidu, 1989), [3H]-naltrindole (Yamamura et al., 1992), [3H]-deltorphin II, [3H]-naltriben (Lever and Scheffel, 1998)[3H]-U69593 (Lahti et al., 1985), [3H]-CI977 (Simonin et al., 2001)[3H]-DAMGO (Goldstein and Naidu, 1989), [3H]-PL017[3H]-N/OFQ (Dooley and Houghten, 1996), [3H]-Leu-N/OFQ, [125I]-Tyr14-N/OFQ

Subtypes of μ (μ1, μ2), δ (δ1, δ2) and κ (κ1, κ2, κ3) receptor have been proposed based primarily on binding studies with poorly selective ligands or in vivo studies. Only three naloxone-sensitive opioid receptors have been cloned, and while the μ-receptor in particular may be subject to extensive alternative splicing, this has not been functionally correlated with any of the proposed subtypes. Thus, there is at present no molecular basis for any of the opioid receptor subtypes, although it remains possible that they are formed by hetero-dimerization of opioid receptors with each other or with other 7TM receptors (Jordan and Devi, 1999). A distinct met-enkephalin receptor lacking structural resemblence to the opioid receptors listed has been identified (ENSG00000060491) and termed an opioid growth factor receptor (see Zagon et al., 2002).

A recent study has observed κ-opioid receptor-dependent phosphorylation of c-Jun terminal kinase by long-lasting κ-opioid antagonists, such as nor-binaltorphimine and GNTI, which may reflect ‘collateral agonist efficacy’ (Bruchas et al., 2007).

Abbreviations: CI977, (5R)-(5α, 7α, 8β)-(-)-N-methyl-N-(7-[1-pyrrolidinyl]-1-oxaspiro[4,5]dec-8-yl)-4-benzofuranacetamide hydrochloride; CTAP, D-Phe-cyc[Cys-Tyr-D-Trp-Arg-Thr-Pen]-Thr-NH2; DAMGO, Tyr-DAla-Gly-[NMePhe]-NH(CH2)2; DPDPE,cyc[DPen2, DPen5]enkephalin; DSBULET, Tyr-DSer(OtBu)-Gly-Phe-Leu-Thr; GNTI, 5′-guanidinyl-17-(cyclopropylmethyl)-6,7-dehydro-4, 5α-epoxy-3, 14-dihydroxy-6, 7–2′, 3′-indolomorphinan; ICI174864,N, N-diallyl-Tyr-Aib-Phe-Leu-OH (Aib is aminoisobutyric acid); J113397, 1-[(3r, 4r)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one; PL017, [N-MePhe3, DPro4]morphiceptin; Ro646198, (1S, 3aS)-8-(2, 3, 3a, 4.5.6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1, 3, 8-triazaspiro[4.5]decan-4-one; SB612111, (-)-cis-1-methyl-7-[[4-(2, 6-dichlorophenyl)pi-peridin-1-yl]methyl]-6, 7, 8, 9-tetrahydro-5H-benzocyclohepten-5-ol; SNC80, (+)-4-[(αR)-α-((2S, 5R)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N, N-diethylbenzamide; U69593, 5α, 7α, 8β-(-)-N-methyl-N-(7-[1-pyrrolidinyl]-1-oxasipro(4, 5)dec-8-yl)benzene acetamide; UFP101, [Nphe1, Arg14, Lys15]nociceptin-NH2; UFP-112, [(pF)Phe4Aib7Arg14Lys15]N/OFQ-NH2

Further Reading

Bailey CP, Connor M (2005). Opioids: cellular mechanisms of tolerance and physical dependence. Curr Opin Pharmacol5: 60–68.

Ballantyne JC, Laforge KS (2007). Opioid dependence and addiction during opioid treatment of chronic pain. Pain129: 235–255.

Cahill CM, Holdridge SV, Morinville A (2007). Trafficking of κ-opioid receptors and other G-protein-coupled receptors: implications for pain and analgesia. Trends Pharmacol Sci28: 23–31.

Chiou LC, Liao YY, Fan PC, Kuo PH, Wang CH, Riemer C et al. (2007). Nociceptin/orphanin FQ peptide receptors: pharmacology and clinical implications. Curr Drug Targets8: 117–135.

Dhawan BN, Cesselin F, Raghubir R, Reisine T, Bradley PB, Portoghese PS et al. (1996). International Union of Pharmacology. XII. Classification of opioid receptors. Pharmacol Rev48: 567–592.

Fichna J, Janecka A, Costentin J, Do Rego JC (2007). The endomorphin system and its evolving neurophysiological role. Pharmacol Rev59: 88–123.

Holzer P (2004). Opioids and opioid receptors in the enteric nervous system: from a problem in opioid analgesia to a possible new prokinetic therapy in humans. Neurosci Lett361: 192–195.

Liu-Chen LY (2004). Agonist-induced regulation and trafficking of κ-opioid receptors. Life Sci75: 511–536.

Pineyro G, Archer-Lahlou E (2007). Ligand-specific receptor states: implications for opiate receptor signalling and regulation. Cell Signal19: 8–19.

Sadee W, Wang D, Bilsky EJ (2005). Basal opioid receptor activity, neutral antagonists, and therapeutic opportunities. Life Sci76: 1427–1437.

Samways DS, Henderson G (2006). Opioid elevation of intracellular free calcium: possible mechanisms and physiological relevance. Cell Signal18: 151–161.

Somogyi AA, Barratt DT, Coller JK (2007). Pharmacogenetics of opioids. Clin Pharmacol Ther81: 429–444.

Tegeder I, Geisslinger G (2004). Opioids as modulators of cell death and survival-unraveling mechanisms and revealing new indications. Pharmacol Rev56: 351–369.

von Zastrow M (2004). A cell biologist's perspective on physiological adaptation to opiate drugs. Neuropharmacology47 (Suppl 1): 286–292.

Waldhoer M, Bartlett SE, Whistler JL (2004). Opioid receptors. Annu Rev Biochem73: 953–990.

Zollner C, Stein C (2007). Opioids. Handb Exp Pharmacol 31–63.

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Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1-S209.

Orexin

Overview: Orexin receptors (provisional nomenclature) are activated by the endogenous polypeptides orexin-A and orexin-B (also known as hypocretin-1 and −2; 33 and 28 aa) derived from a common precursor, orexin (ENSG00000161610), by proteolytic cleavage (Sakurai et al., 1998). Binding to both receptors may be accomplished with [125I]-orexin A (Holmqvist et al., 2001).

NomenclatureOX1OX2
Other namesHypocretin receptor type 1Hypocretin receptor type 2
Ensembl IDENSG00000121764ENSG00000137252
Principal transductionGq/11Gq/11
Rank order of potencyOrexin-A>orexin-BOrexin-A=orexin-B
Selective agonists[Ala11,D-Leu15]orexin-B (Asahi et al., 2003)
Selective antagonistsSB408124 (7.5, Langmead et al., 2004), SB334867A (7.2-7.3, Smart et al., 2001)

The HCRTR2 gene encoding the OX2 receptor has been identified as a possible candidate for inherited narcolepsy (Chemelli et al., 1999; Lin et al., 1999; Siegel, 1999).

Abbreviations: SB334867A, 1-(2-methyylbenzoxanzol-6-yl)-3-[1,5]naphthyridin-4-yl-urea hydrochloride; SB408124, 1-(6,8-difluoro-2-methyl-quinolin-4-yl)-3-(4-dimethylamino-phenyl)-ure

Further Reading

Berridge CW, Espana RA (2005). Hypocretins: waking, arousal, or action? Neuron46: 696–698.

Bingham MJ, Cai J, Deehan MR (2006). Eating, sleeping and rewarding: orexin receptors and their antagonists. Curr Opin Drug Discov Devel9: 551–559.

Harris GC, Aston-Jones G (2006). Arousal and reward: a dichotomy in orexin function. Trends Neurosci29: 571–577.

Levin BE (2006). Orexins: neuropeptides for all seasons and functions. Am J Physiol Regul Integr Comp Physiol291: R885–R888.

Nishino S (2007). The hypothalamic peptidergic system, hypocretin/orexin and vigilance control. Neuropeptides41: 117–133.

Sakurai T (2006). Roles of orexins and orexin receptors in central regulation of feeding behavior and energy homeostasis. CNS Neurol Disord Drug Targets5: 313–325.

Sakurai T (2007). The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci8: 171–181.

Siegel JM (2004). Hypocretin (orexin): role in normal behavior and neuropathology. Annu Rev Psychol55: 125–148.

Siegel JM, Boehmer LN (2006). Narcolepsy and the hypocretin system–where motion meets emotion. Nat Clin Pract Neurol2: 548–556.

Spinazzi R, Andreis PG, Rossi GP, Nussdorfer GG (2006). Orexins in the regulation of the hypothalamic-pituitary-adrenal axis. Pharmacol Rev58: 46–57.

Zeitzer JM, Nishino S, Mignot E (2006). The neurobiology of hypocretins (orexins), narcolepsy and related therapeutic interventions. Trends Pharmacol Sci27: 368–374.

References

Asahi S et al. (2003). Bioorg Med Chem Lett13: 111–113.

Chemelli RM et al. (1999). Cell98: 437–451.

Holmqvist T et al. (2001). Neurosci Lett305: 177–180.

Langmead CJ et al. (2004). Br J Pharmacol141: 340–346.

Lin L et al. (1999). Cell98: 365–376.

Sakurai T et al. (1998). Cell92: 573–585.

Siegel JM (1999). Cell98: 409–412.

Smart D et al. (2001). Br J Pharmacol132: 1179–1182.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

P2Y

Overview: P2Y receptors (provisional nomenclature as agreed by NC-IUPHAR Subcommittee on P2Y Receptors, Abbracchio et al., 2003; 2006) are activated by the endogenous ligands ATP, ADP, UTP, UDP and UDP-glucose. The relationship of many of the cloned receptors to endogenously expressed receptors is not yet established and so it might be appropriate to use wording such as ‘UTP-preferring (or ATP-, etc.) P2Y receptor’ or ‘P2Y1-like', etc., until further, as yet undefined, corroborative critieria can be applied.

NomenclatureP2Y1P2Y2P2Y4P2Y6
Ensembl IDENSG00000169860ENSG00000175591ENSG00000186912ENSG00000171361
Principal transductionGq/11Gq/11Gq/11Gq/11
Rank order of potencyADP>ATPUTP=ATPUTP>ATP (at rat recombinant receptors, UTP=ATP)UDP > > UTP>ATP
Selective agonists2-MeSADP, ADPβS, MRS2365 (Bourdon et al., 2006)UTPγS (Lazarowski et al., 1996), Ap4A (Castro et al., 1992)UTPγS (Lazarowski et al., 1996)UDP, 2-phenacylUDP (El-Tayeb et al., 2006)
Selective antagonistsMRS2500 (8.8, Kim et al., 2003), MRS2279 (8.0, Waldo et al., 2002), MRS2179 (7.0, Boyer et al., 1996), PIT (6.8, Gao et al., 2004)ATP (6.2, Kennedy et al., 2000)MRS2578 (pIC50 7.4, Mamedova et al., 2004)
Probes[3H]-MRS2279 (8 nM, Waldo et al., 2002) [35S]-ADPβS, [35S]-ATPαS, [35S]-dATPαS
NomenclatureP2Y11P2Y12P2Y13P2Y14
Other namesP2YADP,P2TGPR86, GPR94, SP174KIAAA00001, gpr105
Ensembl IDENSG00000176130 ENSG00000174944ENSG00000169313ENSG00000181631 
Principal transductionGs,Gq/11Gi/oGi/oGq/11
Rank order of potencyATP>UTPADP > > ATPADP > > ATPUDP-glucose
Selective agonistsARC67085 (Communi et al., 1999), NAD+ (Moreschi et al., 2006), NAADP+ (Moreschi et al., 2007)ADP, 2-MeSADPMRS2690 (Ko et al., 2007)
Selective antagonistsATP, ARL66096 (Humphries et al., 1995)MRS2211 (Kim et al., 2005)

ARC69931MX shows selectivity for P2Y12 and P2Y13 receptors compared to other P2Y receptors (Takasaki et al., 2001; Marteau et al., 2003).

A 7TM orphan receptor suggested to be a ‘P2Y15’receptor (Inbe et al., 2004) appears not to be a genuine nucleotide receptor (see Abbracchio et al., 2006), but rather responds to dicarboxylic acids (He et al., 2004). Further P2Y-like receptors have been cloned from non-mammalian sources; a clone from chick brain, termed a p2y3 receptor (ENSGALG00000017327), couples to the Gq/11 family of G proteins and shows the rank order of potency ADP>UTP>ATP = UDP (Webb et al., 1996a). In addition, human sources have yielded a clone with a preliminary identification of p2y5 (ENSG00000139679) and contradictory evidence of responses to ATP (Webb et al., 1996b; King and Townsend-Nicholson, 2000). The clone p2y7 (ENSG00000196943), originally suggested to be a P2Y receptor (Akbar et al., 1996), has been shown to encode a leukotriene receptor (Yokomizo et al., 1997). A P2Y receptor that was initially termed a p2y8 receptor (P79928) has been cloned from Xenopus laevis; it shows the rank order of potency ADPβS>ATP = UTP = GTP = CTP = TTP = ITP>ATPγS and elicits a Ca2+-dependent Cl- current in Xenopus oocytes (Bogdanov et al., 1997). The clone termed p2y9 has recently been described as an LPA receptor (Noguchi et al., 2003), while the p2y10 (ENSG00000078589) clone lacks functional data. Diadenosine polyphosphates also have effects on as yet uncloned P2Y-like receptors with the rank order of potency of Ap4A > Ap5A > Ap3A, coupling via Gq/11 (Castro et al., 1992). P2Y-like receptors have recently been described on mitochondria (Belous et al., 2004). CysLT1 and CysLT2 leukotriene receptors respond to nanomolar concentrations of UDP, although they are activated principally by leukotrienes C4 and D4 (Mellor et al., 2001, 2003); Human (ENSG00000144230) and rat GPR17, which are structurally related to CysLT and P2Y receptors, are also activated by leukotrienes as well as UDP and UDP-glucose (Ciana et al., 2006). Activity at the rat GPR17 is inhibited by submicromolar concentrations of MRS2179 and ARL69931 (Ciana et al., 2006).

Abbreviations: ARC67085, 2-propylthio-βγ-dichloromethylene-ATP; AR-C69931MX,N6-(2-methylthioethyl)-2-(3,3,3-trifluoropropylthio)-βγ-dichloromethylene-ATP, also known as cangrelor; 2-MeSADP, 2-methylthio-adenosine-5′-diphosphate; 2-MeSATP, 2-methylthio-adenosine-5′-triphosphate; ARL66096, 2-propylthio-βγ-difluoromethylene ATP (previously FPL66096); ATPγS, adenosine 5′-(3-thio)triphosphate; MRS2179,N6-methyl-2′-deoxyadenosine-3′,5′-bisphosphate; MRS2211, pyridoxal-5′- phosphate-6-azo (2-chloro-5-nitrophenyl)-2,4-disulfonate; MRS2279, 2-chloro-N6-methyl-(N)-methanocarba-2′-deoxyadenosine-3′,5′-bisphosphate; MRS2365, (N)-methanocarba-2-MeSADP; MRS2500,N6-methyl-(N)-methanocarba-2′-deoxyadenosine-3′,5-bisphosphate; MRS2578,N,N”-1,4-butanediyl bis(N'-[3-isothiocynatophenyl)] thiourea; MRS2690, 2-thiouridine-5′-diphosphoglucose; PIT, 2,2′-pyridylisatogen tosylate

Further Reading

Abbracchio MP, Boeynaems JM, Barnard EA, Boyer JL, Kennedy C, Miras-Portugal MT et al. (2003). Characterization of the UDP-glucose receptor (re-named here the P2Y14 receptor) adds diversity to the P2Y receptor family. Trends Pharmacol Sci24: 52–55.

Abbracchio MP, Burnstock G, Boeynaems JM, Barnard EA, Boyer JL, Kennedy C et al. (2006). International Union of Pharmacology LVIII: update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy. Pharmacol Rev58: 281–341.

Burnstock G (2006). Historical review: ATP as a neurotransmitter. Trends Pharmacol Sci27: 166–176.

Burnstock G (2006). Purinergic P2 receptors as targets for novel analgesics. Pharmacol Ther110: 433–454.

Burnstock G (2006). Purinergic signalling. Br J Pharmacol147: S172–S181.

Burnstock G (2007). Purine and pyrimidine receptors. Cell Mol Life Sci64: 1471–1483.

Erb L, Liao Z, Seye CI, Weisman GA (2006). P2 receptors: intracellular signaling. Pflugers Arch452: 552–562.

Volonte C, Amadio S, D'Ambrosi N, Colpi M, Burnstock G (2006). P2 receptor web: complexity and fine-tuning. Pharmacol Ther112: 264–280.

Von Kugelgen I (2006). Pharmacological profiles of cloned mammalian P2Y-receptor subtypes. Pharmacol Ther110: 415–432.

References

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Bogdanov YD et al. (1997). J Biol Chem272: 12583–12590.

Bourdon DM et al. (2006). J Thromb Haemost4: 861–868.

Boyer JL et al. (1996). Mol Pharmacol50: 1323–1329.

Castro E et al. (1992). Br J Pharmacol106: 833–837.

Ciana P et al. (2006). EMBO J25: 4615–4627.

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Inbe H et al. (2004). J Biol Chem279: 19790–19799.

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Kim YC et al. (2005). Biochem Pharmacol70: 266–274.

King BF, Townsend-Nicholson A (2000). J Auton Nerv Syst81: 164–170.

Ko H et al. (2007). J Med Chem50: 2030–2039.

Lazarowski ER et al. (1996). Br J Pharmacol117: 203–209.

Mamedova LK et al. (2004). Biochem Pharmacol67: 1763–1770.

Marteau F et al. (2003). Mol Pharmacol64: 104–112.

Mellor EA et al. (2001). Proc Natl Acad Sci USA98: 7964–7969.

Mellor EA et al. (2003). Proc Natl Acad Sci USA100: 11589–11593.

Moreschi I et al. (2006). Biochem Biophys Res Commun345: 573–580.

Moreschi I et al. (2007). Cell Calcium, in press.

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Waldo GL et al. (2002). Mol Pharmacol62: 1249–1257.

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Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Parathyroid hormone and parathyroid hormone-related peptide

Overview: Parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP) receptors (provisional nomenclature) are activated by precursor-derived peptides: PTH (84 amino acids, ENSG00000152266), PTHrP (141 amino-acids and related peptides (PTHrP-1-36, PTHrP-38-94 and osteostatin (PTHrP-107-139) (ENSG0000087494) and TIP39 (39 amino acids, ENSG00000142538). [125I]-PTH may be used to label both PTH1 and PTH2 receptors.

Although PTH is an agonist at human PTH2 receptors, it fails to activate the rodent orthologues. TIP39 is a weak antagonist at PTH1 receptors (Jonsson et al., 2001).

NomenclaturePTH1PTH2
Other namesPTH/PTHrP
Ensembl IDENSG00000160801ENSG00000144407
Principal transductionGs,Gq/11Gs,Gq/11
Rank order of potencyPTH=PTHrPTIP39, PTH ≫ PTHrP
Selective agonistsTIP39 (Hoare et al., 2000)
Selective antagonistsTIP-9-39 (Jonsson et al., 2001)

Abbreviations: PTH, parathyroid hormone; PTHrP, parathyroid hormone-related peptide; TIP39, tuberoinfundibular protein of 39 residues

Further Reading

Gensure RC, Gardella TJ, Juppner H (2005). Parathyroid hormone and parathyroid hormone-related peptide, and their receptors. Biochem Biophys Res Commun328: 666–678.

Murray TM, Rao LG, Divieti P, Bringhurst FR (2005). Parathyroid hormone secretion and action: evidence for discrete receptors for the carboxyl-terminal region and related biological actions of carboxyl- terminal ligands. Endocr Rev26: 78–113.

Poole KES, Reeve J (2005). Parathyroid hormone—a bone anabolic and catabolic agent. Curr Opin Pharmacol5: 612–617.

Potts JT (2005). Parathyroid hormone: past and present. J Endocrinol187: 311–325.

References

Hoare SR et al. (2000). J Biol Chem275: 27274–27283.

Jonsson KB et al. (2001). Endocrinology142: 704–709.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Platelet-activating factor

Overview: Platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a biologically active phospholipid mediator. PAF acts by binding to a unique G-protein-coupled seven transmembrane receptor (PAF-R) and activates multiple intracellular signaling pathways by coupling to the Gq/11 and Gi/o families of G-proteins. PAF-R is activated by PAF and its metabolically stable analogue mc-PAF. Other suggested endogenous ligands are oxidized phosphatidylcholine (Marathe et al., 1999) and lysophosphatidylcholine (Ogita et al., 1997). It may also be activated by bacterial lipopolysaccharide (Nakamura et al., 1992).

NomenclaturePAF-R
Ensembl IDENSG00000169403
Principal transductionGq/11,Gi,Go
Selective agonistsmc-PAF
Selective antagonistsCV-6209 (9.5), SR27417 (10.0), WEB2086 (8.0), L659989 (8.1), ginkgolide B (6.4)
Radioligand[3H]-PAF (1.6 nM, Fukunaga et al., 2001)

Note that a previously recommended radioligand ([3H]-WEB2086; Kd 44.6 nM) is currently unavailable.

Abbreviations: CV-6209, 2-(N-acetyl-N-[2-methoxy-3-octadecylcarbamoyloxypropoxycarbamoyl]aminomethyl)-1-ethylpyridinium chloride; L659989,trans-2-(3-methoxy-5-methylsulphonyl-4-propoxyphenyl)-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran; mc-PAF, 1-O-alkyl-2-N-methylcarbamoyl-sn-glycero-3-phosphocholine; also known as (methyl)carbam(o)yl-PAF or c-PAF; SR27417,N-(2-dimethylaminoethyl)-N-(3-pyridinylmethyl)(4-[2,4,6-triisopropylphenyl]thoiazol-2-yl)amine; WEB2086, 3-(4-[2-chlorophenyl]-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo [4,3-a][1,4]diazepine-2-yl)-1-(4-morpholinyl)-1-propanone; also known as apafant

Further Reading

Honda Z, Ishii S, Shimizu T (2002). Platelet-activating factor receptor. J Biochem1331: 773–779.

Ishii S, Nagase T, Shimizu T (2002). Platelet-activating factor receptor. Prostaglandins Other Lipid Mediators68: 599–609.

Ishii S, Shimizu T (2000). Platelet-activating factor (PAF) receptor and genetically engineered PAF receptor mutant mice. Prog Lipid Res39: 41–82.

Izumi T, Shimizu T (1995). Platelet-activating factor receptor; gene expression and signal transduction. Biochim Biophys Acta1259: 317–333.

Montrucchio G, Alloatti G, Camussi G (2000). Role of platelet-activating factor in cardiovascular pathophysiology. Physiol Rev80: 1669–1699.

MacLennan KM, Smith PF, Darlington CL (1996). Platelet-activating factor in the CNS. Prog Neurobiol50: 585–596.

Prescott SM, Zimmerman GA, Stafforini DM, McIntyre TM (2000). Platelet-actiating factor and related lipid mediators. Annu Rev Biochem69: 419–445.

Stafforini DM, McIntyre TM, Zimmerman GA, Prescott SM (2003). Platelet-activating factor, a pleiotrophic mediator of physiological and pathological processes. Crit Rev Clin Lab Sci40: 643–672.

Summers JB, Albert DH (1995). Platelet activating factor antagonists. Adv Pharmacol32: 67–168.

References

Fukunaga K et al. (2001). J Biol Chem276: 43025–43030.

Marathe GK et al. (1999). J Biol Chem274: 28395–28404.

Nakamura M et al. (1992). FEBS Lett314: 125–129.

Ogita T et al. (1997). Am J Physiol272: H17–H24.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Prostanoid

Overview: Prostanoid receptors (nomenclature agreed by the NC-IUPHAR Subcommittee on Prostanoid Receptors, see Coleman et al., 1994) are activated by the endogenous ligands prostaglandin (PG) D2 (D), PGE2 (E), PGF (F), PGH2 (H), prostacyclin [PGI2 (I)] and thromboxane A2 (T). Measurement of the potency of PGI2 and TXA2 is hampered by their instability in physiological salt solution; they are often replaced by cicaprost and U46619, respectively, in receptor characterization studies.

NomenclatureDP1DP2FPIPTP
Other namesCRTh2, GPR44
Ensembl IDENSG00000168229ENSG00000183134ENSG00000122420ENSG00000160013ENSG00000006638
Principal transductionGsGi/oGq/11GsGq/11
Rank order of potencyD>>E>FI>,TD>>F, E>I, TF>D>E>I,TI>>D,E,F>TT=H>>D,E,F,I
Selective agonistsL644698, BW245C, ZK118182, RS93520, SQ2798613,14-dihydro-15-oxoPGD2, 15R-15-methyl PGD2 (Hata et al., 2003; Monneret et al., 2003)Fluprostenol, latanoprostCicaprost, AFP-07, BMY45778 (Seiler et al., 1997)U46619, STA2, I-BOP, AGN192093
Selective antagonistsBWA868C (9.3, Giles, 1989), S5751 (8.8, Arimura et al., 2001), ZK138357 (7.3, Lydford et al., 1996)Ramatroban (Sugimoto et al., 2003), CAY10471 (Mathiesen et al, 2006)RO1138452 (8.8, Bley et al., 2006)BMS180291 (9.3–10.0), ONO3708 (8.9), GR32191 (8.3–9.4, Lumley et al., 1989), SQ29548 (8.1–9.1, Swayne et al., 1988)
Probes[3H]-PGD2 (13–34 nM)[3H]-PGD2 (6–11 nM)[3H]-PGF (2–4 nM), [3H]-(+)-fluprostenol (34 nM)[3H]-Iloprost (1–20 nM)[3H]-SQ29548 (5–40 nM), [125I]-SAP (0.2–1.0 nM), [125I]-I-BOP (0.3–5.0 nM)

Ramatroban is also a TP receptor antagonist. Cicaprost exhibits moderate EP4 receptor agonist potency (Abramovitz et al., 2000). Iloprost also binds to EP1 receptors. The TP receptor exists in α and β isoforms due to alternative splicing of the cytoplasmic tail (Raychowdhury et al., 1994).

NomenclatureEP1EP2EP3EP4
Ensembl IDENSG00000160951ENSG00000125384ENSG00000050628ENSG00000171522
Principal transductionGq/11GsGi/oGs
Rank order of potencyE>F,I>D,TE>F,I>D,TE>F,I>D,TE>F,I>D,T
Selective agonists17-Ph-ω-trinor-PGE2, ONO-DI-004Butaprost, AH13205, ONO-AE1-259Sulprostone, SC46275, ONO-AE-248ONE-AE1-329
Selective antagonistsONO8711 (9.2), SC51322 (8.8)L798106 (7.7)GW627368 (9.2), ONO-AE3–208 (8.5), L161982 (7.6)
Probes[3H]-PGE2 (1–25 nM)[3H]-PGE2 (5–22 nM)[3H]-PGE2 (03–7 nM)[3H]-PGE2 (0.6–24 nM)

17-Ph-ω-trinor-PGE2 also shows agonist activity at EP3 receptors. Sulprostone also has affinity for EP1 receptors. Butaprost and SC46275 may require de-esterification within tissues to attain full agonist potency. There is evidence for subtypes of FP (Liljebris et al., 1995), IP (Takechi et al., 1996; Wise et al., 1995) and TP (Krauss et al., 1996) receptors. mRNA for the EP1 and EP3 receptors undergo alternative splicing to produce two (Okuda-Ashitaka et al., 1996) and at least six variants, respectively, which can interfere with signalling (Okuda-Ashitaka et al., 1996) or generate complex patterns of G-protein (Gi/o, Gq/11, Gs and G12,13) coupling (e.g. Kotani et al., 1995; Negishi et al., 1995). The possibility of additional receptors for the isoprostanes has been suggested (Pratico et al., 1996).

Abbreviations: AFP-07, 7,7-difluoro-16S,20-dimethyl-18,19-didehydro-PGI2; AGN192093, (Z)-7-([1α,5α,6α,7β]-7-[{1E,3S}-3-hydroxy-1-octe-nyl]-3-oxo-2,4-dioxobicyclo[3.2.1]oct-6-yl)-5-heptenol; AH13205,trans-2-(4-[1-hydroxyhexyl]phenyl)-5-oxocyclopentane-heptanoic acid; AH23848, (1α[z],2β,5α)-(±)-7-(5-[{(1,1′-biphenyl)-4-yl}methoxy]-2-[4-morpholinyl]-3-oxocyclopentyl)-4-heptenoate; BMS180291, (1s-(1α,2α,3α,4α)-2-([3-{4-([pentylamino]carbonyl)-2-oxazolyl}-7-oxabicyclo{2.2.1}hept-2-yl]methyl)benzenepropanoic acid, also known as ifetroban; BMY45778, 3-(4-[4,5-diphenyl-2-oxazolyl]-5-oxazolyl)phenoxyacetic acid; BW245C, 5-(6-carboxyhexyl)- 1-(3-cyclohexyl-3-hydroxypropyl) hydantoin; BWA868C, 3-benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexyl-2-hydroxyethylamino)hydantoin; CAY10471, (+)-3-([{4-fluorophenyl}-sulfonyl]methylamino)-1,2,3,4-tetrahydro-9H-carbazole-9-acetic acid; GR32191, [1R-[1(Z),2α,3β,5]]-(+)-7-[5-[[(1,1′-biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoic acid; GW627368,N-(2-[4-{4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl}phe-nyl]-acetyl)benzenesulphonamide; I-BOP, (1S-[1α,2β{5z},3α[1e,3 s,], 4α])-7-(3-[hydroxy-4-{4′-iodophenoxy}-1-butenyl]-7-oxabicyclo[2.2.1]hept-2-yl)-5-heptanoate; L161982, 5-butyl-2,4-dihydro-[[2′-[N-(5-methyl-2-thiophenecarbonyl)sulphamoyl]biphenyl-4-yl]methyl]-2-[(2-trifluoro-methyl)phenyl]-1,2,4-triazol-3-one; L644698, 4-(3-{3-[3-hydroxyoctyl]-4-oxo-2-thiazolidinyl}propyl)benzoate racemate; L798106, 5-bromo-2-methoxy-N-[3-(naphthalen-2-yl-methylphenyl)-acryloyl]-benzenesulphonamide; ONO3708, (9,11)-(11,12)-dideoxa-9α,11α-dimethylmethano-11,12-methano-13,14-dihydro-13-aza-14-oxo-15-cyclopentyl-16,17,18,19,20-pentanor-15-epi-TXA2; ONO8711, 6-[(2S,3S)-3-(4-chloro-2-methyl-phenylsulphonylaminomethyl)-bicyclo[2.2.2]octan-2-yl]-5Z-hexenoic acid; ONO-DI-004, 17S-17,20-dimethyl-2,5-ethano-6-oxo PGE1; ONO-AE-248, 11,15-O-dimethyl-PGE2; ONO-AE1-259, 16s-9-deoxy-9β-chloro-15-deoxy-16-hydroxy-17,17-propano-19,20-didehydro-PGE2; ONO-AE1-329, 16-(3-methoxymethyl)phenyl-ω-tetranor-3,7-dithia-PGE1; ONO-AE3-208, 2-(2-(2-methyl-2-naphth-1-ylacetylamino)-phenylmethyl)-benzoic acid; RO1138452, 4,5-dihydro-1H-imidazol-Z-yl)-[4-(4-isopropoxybenzyl)phenyl]amine; RS93520, Z-4-([C3′S,1R,2R,3S,6R]-2C3′-cyclo-hexyl-3′-hydroxyprop-1-ynyl)-3-hydroxybicyclo(4.2.0)oct-7-ylidene butyrate; SAP, 7-([1R,2S,3S,5R]-6,6-dimethyl-3-benzenesulphonamino-bicyclo[3.1.1]hept-2-yl)-5z-heptenoic acid; SC46275, methyl-7-(2β-[6-{1-cyclopenten-1-yl}-4R-hydroxy-4-methyl-1e,5e-hexadienyl]-3α-hydroxy-5-oxo-1R,1α-cyclopentyl)-4z-heptenoic acid; SC51322, 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-[3-[furanylmethyl)- thio] 1-oxopropyl]hydrazide; SQ29548, (1S-[1α,2β{5z},3β,4β])7-(3-[{2-(phenylamino)carbonyl}hydrazino]methyl)-7-oxabicyclo[2.2.1]hept-2-yl-5-heptenoate; S5751, ((Z)-7-[1R,2R,3S,5S)-2-(5-hydroxybenzo[b]thiophen-3-ylcarbonylamino)-10-norpinan-3-yl]hept-5-enoic acid); SQ27986, [1S-[1B,2B(5Z),3A(1E,3S)4B]]7-[3-(3-cyclohexyl-3-hydroxy-1-propenyl)-7-oxabicyclo[2.2.1]hept-2-y]5-heptenoic acid; STA2, 11α-carba-9α,11β-thia-Txa2; U46619, 11α,9α-epoxymethano-PGH2; ZK 118182, (5Z,13E)-(9R,11R,15S)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5,13-prostadienoic acid; ZK138357, (5Z)-7-([2RS,4S,5S]-2-[2-chlorophenyl]-5-[{1E}-{3R,S}-3-hydroxy-3-cyclohexyl-1-propenyl] 1,3-dioxolan-4-yl)-5-heptanoic acid

Further Reading

Bos CL, Richel DJ, Ritsema T, Peppelenbosch MP, Versteeg HH (2004). Prostanoids and prostanoid receptors in signal transduction. Int J Biochem Cell Biol36: 1187–1205.

Breyer RM, Bagdassarian CK, Myers SA, Breyer MD (2001). Prostanoid receptors: subtypes and signaling. Annu Rev Pharmacol Toxicol41: 661–690.

Coleman RA, Smith WL, Narumiya S (1994). VIII. International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes. Pharmacol Rev46: 205–229.

Flavahan NA (2007). Balancing prostanoid activity in the human vascular system. Trends Pharmacol Sci28: 106–110.

Hata AN, Breyer RM (2004). Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation. Pharmacol Ther103: 147–166.

Kostenis E, Ulven T (2006). Emerging roles of DP and CRTH2 in allergic inflammation. Trends Mol Med12: 148–158.

Pettipher R, Hansel TT, Armer R (2007). Antagonism of the prostaglandin D2 receptors DP1 and CRTH2 as an approach to treat allergic diseases. Nat Rev Drug Discov6: 313–325.

Sugimoto Y, Narumiya S (2007). Prostaglandin E receptors. J Biol Chem282: 11613–11617.

References

Abramovitz M et al. (2000). Biochim Biophys Acta1483: 285–293.

Arimura A et al. (2001). J Pharmacol Exp Ther298: 411–419.

Bley KR et al. (2006). Br J Pharmacol147: 335–345.

Giles H et al. (1989). Br J Pharmacol96: 291–300.

Hata AN et al. (2003). J Pharmacol Exp Ther306: 463–470.

Kotani M et al. (1995). Mol Pharmacol48: 869–879.

Krauss AH et al. (1996). Br J Pharmacol117: 1171–1180.

Liljebris C et al. (1995). J Med Chem38: 289–304.

Lumley P et al. (1989). Br J Pharmacol97: 783–794.

Lydford SJ et al. (1996). Br J Pharmacol117: 190P–190.

Mathiesen JM et al. (2006). Mol Pharmacol.69: 1441–1453.

Monneret G et al. (2003). J Pharmacol Exp Ther304: 349–355.

Negishi M et al. (1995). J Biol Chem270: 16122–16127.

Okuda-Ashitaka E et al. (1996). J Biol Chem271: 31255–31261.

Pratico D et al. (1996). J Biol Chem271: 14916–14924.

Raychowdhury MK et al. (1994). J Biol Chem269: 19256–19261.

Seiler SM et al. (1997). Life Sci74: 135–141.

Swayne GT et al. (1988). Eur J Pharmacol152: 311–319.

Takechi H et al. (1996). J Biol Chem271: 5901–5906.

Wise H et al. (1995). Eur J Pharmacol278: 265–269.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Proteinase-activated

Overview: Proteinase-activated receptors (PARs, nomenclature as agreed by NC-IUPHAR Subcommittee on Protease-activated Receptors, see Hollenberg & Coughlan, 2002) are activated by proteolytic cleavage of their amino terminal exodomains. Alternative endogenous proteinases or ligands to thrombin for PAR1, PAR3 or PAR4 have not been demonstrated. Activation of PAR2 by trypsin or tryptase release in vivo is yet to be demonstrated. Several proteases, including cathepsin G and chymotrypsin, have an inhibitory effect at the PAR1 receptor such that they cleave the exodomain of the receptor without inducing activation, thereby preventing activation by thrombin but not by agonist peptides. The role of such an action in vivo is unclear. Agonist protease-induced hydrolysis is thought to unmask a tethered ligand at the exposed amino terminus, which acts intramolecularly at the binding site in the body of the receptor to effect transmembrane signalling. Tethered ligand sequences at human PAR1-4 are SFLLRN, SLIGKV, TFRGAP and GYPGQV, respectively. With the exception of PAR3, these synthetic peptide sequences (as carboxyl terminal amides) are able to act as agonists at their respective receptors.

NomenclaturePAR1PAR2PAR3PAR4
Other namesThrombin receptor, PAR-1, PAR1PAR-2, PAR2Thrombin receptor, PAR-3, PAR3Thrombin receptor, PAR-4, PAR4
Ensembl IDENSG00000181104ENSG00000164251ENSG00000164220ENSG00000127533
Principal transductionGq/11/Gi/o/G12/13Gq/11/Gi/oGq/11/Gi/oGq/11/Gi/o
Agonist proteasesThrombin, trypsinTrypsin, tryptaseThrombin, trypsin, factor XaThrombin, trypsin
Selective agonistsTFLLR-NH2SLIGRL, SLIGKVGYPGQV, GYPGKF
Selective antagonistsRWJ56110 (Andrade-Gordon et al., 1999)
Probes[3H]-haTRAP (Ahn et al., 1997)Trans-cinnamoyl-LIGRLO[N-[3H]-propionyl]-NH2 (Al Ani et al., 1999)

TFLLR-NH2 is selective relative to the PAR2 receptor (Blackhart et al., 1996; Kawabata et al., 1999). Thrombin is inactive at the PAR2 receptor.

Abbreviations: [3H]-haTRAP, Ala-p-fluoroPhe-Ala-Arg-cyclohexylAla-homoArg-[3H]-Tyr-amide; RWJ56110, (αS)-N-([1S]-3-amino-1-[{(phenyl-methyl)amino}propyl]-a-[{(1-[{2,6-dichlorophenyl}methyl]-3-[1-pyrrolidinylmethyl]-1H-indol-6-yl)amino}carbonyl]amino)-3,4-difluoro-benzene-propanamide

Further Reading

Barry GD, Le GT, Fairlie DP (2006). Agonists and antagonists of protease activated receptors (PARs). Curr Med Chem13: 243–265.

Bushell T (2007). The emergence of proteinase-activated receptor-2 as a novel target for the treatment of inflammation-related CNS disorders. J Physiol581: 7–16.

Chackalamannil S (2006). Thrombin receptor (protease activated receptor-1) antagonists as potent antithrombotic agents with strong antiplatelet effects. J Med Chem49: 5389–5403.

Cirino G, Vergnolle N (2006). Proteinase-activated receptors (PARs): crossroads between innate immunity and coagulation. Curr Opin Pharmacol6: 428–434.

Coughlin SR (2005). Protease-activated receptors in hemostasis, thrombosis and vascular biology. J Thromb Haemost3: 1800–1814.

Hirano K (2007). The roles of proteinase-activated receptors in the vascular physiology and pathophysiology. Arterioscler Thromb Vasc Biol27: 27–36.

Hollenberg MD (2005). Physiology and pathophysiology of proteinase-activated receptors (PARs): proteinases as hormone-like signal messengers: PARs and more. J Pharmacol Sci97: 8–13.

Hollenberg MD, Compton SJ (2002). International Union of Pharmacology. XXVIII. Proteinase-activated receptors. Pharmacol Rev54: 203–217.

Leger AJ, Covic L, Kuliopulos A (2006). Protease-activated receptors in cardiovascular diseases. Circulation114: 1070–1077.

Moffatt JD (2007). Proteinase-activated receptors in the lower urinary tract. Naunyn Schmiedebergs Arch Pharmacol375: 1–9.

Steinberg SF (2005). The cardiovascular actions of protease-activated receptors. Mol Pharmacol67: 2–11.

Steinhoff M, Buddenkotte J, Shpacovitch V, Rattenholl A, Moormann C, Vergnolle N et al. (2005). Proteinase-activated receptors: transducers of proteinase-mediated signaling in inflammation and immune response. Endocr Rev26: 1–43.

References

Ahn HS et al. (1997). Mol Pharmacol51: 350–356.

Al Ani B et al. (1999). J Pharmacol Exp Ther290: 753–760.

Andrade-Gordon P et al. (1999). Proc Natl Acad Sci USA96: 12257–12262.

Blackhart BD et al. (1996). J Biol Chem271: 16466–16471.

Kawabata A et al. (1999). J Pharmacol Exp Ther288: 358–370.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Prokineticin

Overview: Prokineticin receptors (PKR, provisional nomenclature) respond to the cysteine-rich 81-86 amino-acid peptides prokineticin-1 (PK1, also known as endocrine-gland-derived vascular endothelial growth factor, mambakine, ENSG00000143125) and prokineticin-2 (PK2, protein Bv8 homolog, ENSG00000163421). An orthologue of PK1 from black mamba (Dendroaspis polylepis) venom, mamba intestinal toxin 1 (MIT1, Schweitz et al., 1999) is a potent, non-selective agonist at PKR receptors (Masuda et al., 2002), while Bv8, an orthologue of PK2 from amphibians (Bombina sp., Mollay et al., 1999), is equipotent at recombinant PKR1 and PKR2 receptors (Negri et al., 2005), and has high potency in macrophage chemotaxis assays, which are lost in PKR1-null mice (Martucci et al., 2006).

NomenclaturePKR1PKR2
Other namesPK-R1, GPR73 (Lin et al., 2002; Soga et al., 2002),PK-R2, GPR73a (Lin et al., 2002), GPRg2
 G-protein coupled receptor ZAQ (Masuda et al., 2002)(Soga et al., 2002), I5E (Masuda et al., 2002)
Ensembl IDENSG00000169618ENSG00000101292
Principal transductionGq/11 (Lin et al., 2002; Masuda et al., 2002)Gq/11 (Lin et al., 2002; Masuda et al., 2002)
Rank order of potencyPK2 ≥ PK1 (Lin et al., 2002; Masuda et al., 2002; Soga et al., 2002)PK2 ≥ PK1 (Lin et al., 2002; Masuda et al., 2002; Soga et al., 2002)

Abbreviations: PK1, prokineticin 1; PK2, prokineticin 2

Further Reading

LeCouter J, Ferrara N (2003). EG-VEGF and Bv8. a novel family of tissue-selective mediators of angiogenesis, endothelial phenotype, and function. Trends Cardiovasc Med13: 276–282.

Maldonado-Perez D, Evans J, Denison F, Millar RP, Jabbour HN (2007). Potential roles of the prokineticins in reproduction. Trends Endocrinol Metab18: 66–72.

Zhou QY, Cheng MY (2005). Prokineticin 2 and circadian clock output. FEBS J272: 5703–5709.

References

Lin DC et al. (2002). J Biol Chem277: 19276–19280.

Martucci C et al. (2006). Br J Pharmacol147: 225–234.

Masuda Y et al. (2002). Biochem Biophys Res Commun293: 396–402.

Mollay C et al. (1999). Eur J Pharmacol374: 189–196.

Negri L et al. (2005). Br J Pharmacol146: 625–632.

Schweitz H et al. (1999). FEBS Lett461: 183–188.

Soga T et al. (2002). Biochim Biophys Acta1579: 173–179.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Relaxin family peptide

Relaxin family peptide receptors (RXFP, nomenclature as approved by the NC-IUPHAR committee on relaxin family peptide receptors, Bathgate et al. 2006) may be divided into two groups RXFP1/2 and RXFP3/4. Endogenous agonists at these receptors are a number of heterodimeric peptide hormones analogous to insulin: H1 relaxin [ENSG00000107018], H2 relaxin [ENSG00000107014], H3 relaxin [also known as INSL7, ENSG00000171136], insulin-like peptide (INSL) 3 [OTTHUMG00000070952] and INSL5 [ENSG00000172410].

Species homologues of relaxin have distinct pharmacology—H2 relaxin interacts with RXFP1 and RXFP2, mouse and rat relaxin selectively bind to and activate RXFP1 (Scott et al., 2005a) and porcine relaxin may have a higher efficacy than H2 relaxin (Halls et al., 2005). H3 relaxin has differential affinity for RXFP2 receptors between species; mouse and rat RXFP2 have a higher affinity for H3 relaxin (Scott et al., 2005b). At least two binding sites have been identified on the RXFP1 and RXFP2 receptors: a high-affinity site in the leucine-rich repeat region of the ectodomain and a somewhat lower-affinity site located in the surface loops of the transmembrane (Sudo et al., 2003; Halls et al., 2005). The unique N-terminal LDLa module of RXFP1 and RXFP2 directs receptor signalling (Scott et al., 2007).

NomenclatureRXFP1RXFP2
Other namesRelaxin receptor, LGR7, leucine-rich repeat-containing G-protein-coupled receptor 7, RX1INSL3 receptor, LGR8, leucine-rich repeat-containing G-protein-coupled receptor 8, GREAT, RX2
Ensembl IDENSG00000171509ENSG00000133105
Principal transductionGs, GαoB, Gαi3 (Halls et al., 2006; Hsu et al., 2002)Gs, GαoB (Halls et al., 2006; Kumagai et al., 2002)
Rank order of potencyH2 relaxin>H3 relaxin>>INSL3 (Sudo et al., 2003)INSL3>H2 relaxin>>H3 relaxin (Kumagai et al., 2002; Sudo et al., 2003)
AntagonistsLGR7-truncate (Scott et al., 2007)INSL3 B-chain analog (Del Borgo et al., 2006), (des 1-8) A-chain INSL3 analog (Bullesbach and Schwabe, 2000)
Probes[33P]-H2 relaxin (0.2 nM; Sudo et al., 2003)[33P]-H2 relaxin (1.06 nM; Sudo et al., 2003), [125I]-INSL3 (0.1 nM; Muda et al., 2005)

Mutations in INSL3 and LGR8 (RXFP2) have been reported in populations of patients with cryptorchidism (Ferlin et al., 2003). Numerous splice variants of the human RXFP1 and RXFP2 receptors have been identified, none of which bind relaxin family peptides (Muda et al., 2005). Splice variants of RXFP1 encoding the N-terminal LDLa module act as antagonists of RXFP1 signalling (Scott et al., 2005b). Gain-of-function receptor mutants increase cAMP accumulation in cell lines (Hsu et al., 2000; Hsu et al., 2002).

NomenclatureRXFP3RXFP4
Other namesRelaxin 3 receptor, GPCR135, somatostatin and angiotensin-like peptide receptor SALPR, RX3INSL5 receptor, GPCR142, GPR100, relaxin 3 receptor 2, RX4
Ensembl IDENSG00000182631ENSG00000173080
Principal transductionGi/o (Matsumoto et al., 2000; van der Westhuizen et al., 2005)Gi/o (Liu et al., 2003b; van der Westhuizen et al., 2007)
Rank order of potencyH3 relaxin>H3 relaxin B chain (Liu et al., 2003a)INSL5 = H3 relaxin>H3 relaxin B chain (Liu et al., 2003b, 2005a)
AntagonistsINSL5 (Liu et al., 2005a), R3(BΔ23-27)R/I5 chimeric peptide (Kuei et al., 2007)R3(BΔ23-27)R/I5 chimeric peptide (Kuei et al., 2007)
Probes[125I]-H3 relaxin (0.3 nM; Liu et al., 2003a), [125I]-H3-B/INSL5 A chimera (0.5 nM; Liu et al., 2005b)[125I]-H3 relaxin (0.2 nM; Liu et al., 2003b), [125I]-H3-B/INSL5 A chimera (1.2 nM; Liu et al., 2005b)

H3 relaxin acts as an agonist at both RXFP3 and RXFP4 whereas INSL5 is an agonist at RXFP4 and an antagonist at RXFP3. Current studies indicate that other relaxins and related peptides have little or no action at RXFP3 and RXFP4. Unlike RXFP1 and RXFP2 both RXFP3 and RXFP4 are encoded by a single exon and therefore no splice variants exist. The rat RXFP3 sequence has two potential start codons that encode RXFP3L and RXFP3S with the longer variant having an additional 7 amino-acids at the N-terminus. It is not known which variant is expressed. Rat and dog RXFP4 sequences are pseudogenes (Wilkinson et al., 2005).

Abbreviations: H2 relaxin, human gene 2 relaxin; H3 relaxin, human gene 3 relaxin; INSL3, insulin-like peptide 3; INSL5, insulin-like peptide 5

Further Reading

Bathgate RA, Ivell R, Sanborn BM, Sherwood OD, Summers RJ (2006). International Union of Pharmacology LVII: Recommendations for the nomenclature of receptors for relaxin family peptides. Pharmacol Rev58: 7–31.

Bathgate RAD, Hsueh AJW, Sherwood OD (2005). Physiology and molecular biology of the relaxin peptide family. In: Neill JD (ed). Knobil and Neill's Physiology of Reproduction, 3rd edn, Academic Press: New York, pp 679–768.

Conrad KP, Novak J (2004). Emerging role of relaxin in renal and cardiovascular function. Am J Physiol -Regul Integr Comp Physiol287: R250–R261.

Dschietzig T, Bartsch C, Baumann G, Stangl K (2006). Relaxin-a pleiotropic hormone and its emerging role for experimental and clinical therapeutics. Pharmacol Ther112: 38–56.

Halls ML, van der Westhuizen ET, Bathgate RA, Summers RJ (2007). Relaxin family peptide receptors—former orphans reunite with their parent ligands to activate multiple signalling pathways. Br J Pharmacol150: 677–691.

Samuel CS, Du XJ, Bathgate RA, Summers RJ (2006). Relaxin’ the stiffened heart and arteries: The therapeutic potential for relaxin in the treatment of cardiovascular disease. Pharmacol Ther112: 529–552.

van der Westhuizen ET, Summers RJ, Halls ML, Bathgate RA, Sexton PM (2007). Relaxin receptors—new drug targets for multiple disease states. Curr Drug Targets8: 91–104.

References

Bullesbach EE, Schwabe C (2000). J Biol Chem275: 35276–35280.

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Wilkinson TN et al. (2005). BMC Evol Biol5: 14.

Citation Information

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Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Somatostatin

Overview: Somatostatin (somatotropin release inhibiting factor) is an abundant neuropeptide, which acts on five subtypes of somatostatin receptor (sst1 - sst5; nomenclature approved by the NC-IUPHAR Subcommittee on Somatostatin Receptors, see Hoyer et al., 2000). Activation of these receptors produces a wide range of physiological effects throughout the body. The relationship of the cloned receptors to endogenously expressed receptors is not yet well established in some cases. Endogenous ligands for these receptors are somatostatin-14 (SRIF-14) and somatostatin-28 (SRIF-28). Cortistatin (CST-14) has also been suggested to be an endogenous ligand for somatostatin receptors (Delecea et al., 1996).

Nomenclaturesst1sst2sst3sst4sst5
Alternative namesSSTR1, SRIF2, SRIF2ASSTR2, SRIF1, SRIF1ASSTR3, SRIF1, SRIF1CSSTR4, SRIF2, SRIF2BSSTR5, SRIF1, SRIF1B
Ensembl IDENSG00000139874ENSG00000180616ENSG00000183473ENSG00000132671ENSG00000162009
Principal transductionGiGiGiGiGi
Selective agonistsdes-Ala1, 2, 5-[DTrp8,Iamp9]SRIF, L797591Octreotide, seglitide, BIM23027, L054522L796778NNC269100, L803087BIM23268, BIM23052, L817818
Selective antagonistsCyanamid 154806 (7.7-8.0)BIM23056 (7.4-8.3)
Probes[125I]-[Tyr3]octreotide (0.13 nM) [125I]-BIM23027[125I]-[Tyr3]octreotide (0.23 nM)

[125I]-[Tyr11]SRIF-14, [125I]-LTT-SRIF-28, [125I]-CGP23996 and [125I]-[Tyr10]CST-14 may be used to label somatostatin receptors nonselectively; BIM23052 is said to be selective in rat but not human receptor (Patel and Srikant, 1994). A number of nonpeptide subtype-selective agonists have been synthesised (see Rohrer et al., 1998).

Abbreviations: BIM23027, cyc(N-Me-Ala-Tyr-D-Trp-Lys-Abu-Phe); BIM23052, DPhe-Phe-Phe-DTrp-Lys-Thr-Phe-Thr-NH2; BIM23056, DPhe-Phe-Tyr-DTrp-Lys-Val-Phe-dNal-NH2; BIM23268, cyc(Cys-Phe-Phe-D-Trp-Lys-Thr-Phe-Cys)-NH2; CGP23996, cyc(Asn-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Tyr-Thr-Ser); Cyanamid 154806, Ac-(4-NO2-Phe)-cyc(D-Cys-Tyr-D-Trp-Lys-Thr-Cys)-D-Tyr-NH2; L797591, (2R)-N-(6-amino-2,2,4-trimethylhex-yl)-3-(1-naphthyl)-2-({[(2-phenylethyl)2-pyridin-2-ylethyl)amino]carbonyl}amino)propanamide; L054522, tert-butyl(bS)-b-methyl-N{[4-(2-oxo-2,3,-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]carbonyl}-D-tryptophyl-L-lysinate; L796778, methyl(2S)-6-amino-2-[((2R)-2-{[({(1S)-1-benzyl-2-[(4-nitrophenyl)amino]-2-oxoethyl}amino)carbonyl]amino}hexanoyl)amino]hexanoate; L803087, methyl(2S)-5-{[amino(imino)methyl]amino}-2-{[4-(5,7-difluoro-2-phenyl-1H-indol-3-yl)butanoyl]amino}pentanoate; L817818, (2R)-2-aminopropyl N2-{[2-(2-naphthyl)-1H-benzo[g]indo-3-yl]acetyl}-L-lysinat; LTT-SRIF-28, [Leu8,DTrp22,DTyr25]SRIF-28; NNC269100, 1-[3-[N-(5-bromopyridin-2-yl)-N-(3,4-dichlorobenzyl)amino]-propyl]-3-[3-(1H-imidazol-1-yl)propyl]thiourea

Further Reading

Crider AM, Witt KA (2007). Somatostatin sst4 ligands: chemistry and pharmacology. Mini Rev Med Chem7: 213–220.

Csaba Z, Dournaud P (2001). Cellular biology of somatostatin receptors. Neuropeptides35: 1–23.

Dasgupta P (2004). Somatostatin analogues: multiple roles in cellular proliferation, neoplasia, and angiogenesis. Pharmacol Ther102: 61–85.

Hannon JP, Nunn C, Stolz B, Bruns C, Weckbecker G, Lewis I et al. (2002). Drug design at peptide receptors - somatostatin receptor ligands. J Mol Neurosci18: 15–27.

Hoyer D, Epelbaum J, Feniuk W, Humphrey PPA, Meyerhof W, O'Carroll AM et al. (2000). Somatostatin receptors. In: Watson SP, Girdlestone D (eds). The IUPHAR Compendium of Receptor Characterization and Classification, 2nd edn. IUPHAR Media: London, pp 354–364.

Lahlou H, Guillermet J, Hortala M, Vernejoul F, Pyronnet S, Bousquet C et al. (2004). Molecular signalling of somatostatin receptors. Ann NY Acad Sci1014: 121–131.

Moller LN, Stidsen CE, Hartmann B, Holst JJ (2003). Somatostatin receptors. Biochim Biophys Acta1616: 1–84.

Olias G, Viollet C, Kusserow H, Epelbaum J, Meyerhof W (2004). Regulation and function of somatostatin receptors. J Neurochem89: 1057–1091.

Patel YC (1999). Somatostatin and its receptor family. Front Neuroendocrinology20: 157–198.

Patel YC, Greenwood MT, Panetta R, Demchyshyn L, Niznik H, Srikant CB (1995). The somatostatin receptor family. Life Sci57: 1249—1265.

Rashid AJ, O'Dowd BF, George SR (2004). Minireview: Diversity and complexity of signaling through peptidergic G protein-coupled receptors. Endocrinology145: 2645–2652.

Van der Hoek J, Hofland LJ, Lamberts SW (2005). Novel subtype specific and universal somatostatin analogues: clinical potential and pitfalls. Curr Pharm Des11: 1573–1592.

Weckbecker G, Lewis I, Albert R, Schmid HA, Hoyer D, Bruns C (2003). Opportunities in somatostatin research: Biological, chemical and therapeutic aspects. Nat Rev Drug Discovery2: 999–1017.

References

Delecea L et al. (1996). Nature381: 242–245.

Patel YC, Srikant CB (1994). Endocrinology135: 2814–2817.

Rohrer SP et al. (1998). Science282: 737–740.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Sphingosine-1-phosphate

Overview: Sphingosine-1-phosphate (S1P) receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Lysophospholipid receptors; see Chun et al., 2002) are activated by the endogenous lipid derivatives S1P and sphingosylphosphorylcholine (SPC). S1P has also been described to act at intracellular sites (see Hla et al., 1999; Spiegel and Milstein, 2003), although most cellular phenomena ascribed to S1P can be explained by receptor-mediated mechanisms. The relationship between recombinant and endogenously expressed receptors is unclear. Radioligand binding has been conducted in heterologous expression systems using [32P]-S1P (e.g. Okamoto et al., 1998). In native systems, analysis of binding data is complicated by metabolism and high levels of nonspecific binding. Targeted deletion of several S1P receptors has clarified signalling pathways and physiological roles.

NomenclatureS1P1S1P2S1P3S1P4S1P5
Other namesedg1, lpB1edg5, lpB2, AGR16, H218edg3, lpB3edg6, lpC1edg8, lpB4, NRG-1
Ensembl IDENSG00000170989ENSG00000175898ENSG00000186354ENSG00000125910ENSG00000180739
Principal transductionGi/oGq, G12/13, GsGq, Gi/o, GsGi/o, G12/13, GsGi/o, G12/13
Rank order of potencyS1P>SPCS1P>SPC (Okamoto et al., 1998)S1P>SPC (Okamoto et al., 1998)S1P, SPCS1P, SPC
Selective agonistsSEW2871 (Sanna et al., 2004)
Selective antagonistsJTE013 (Osada et al., 2002)

The novel immunomodulator fingolimod (FTY720) may be phosphorylated in vivo (Albert et al., 2005) to generate a relatively potent agonist with activity at SIP1, SIP3, SIP4 and SIP5 receptors (Brinkmann et al., 2002; Mandala et al., 2002).

Abbreviations: JTE013, pyrazolopyridine analog; SEW2871, 5-(4-phenyl-5-trifluoromethylthiophen-2-yl)-3-(3-trifluoromethylphenyl)-(1,2,4)-oxadiazole

Further Reading

Anliker B, Chun J (2004). Lysophospholipid G protein-coupled receptors. J Biol Chem279: 20555–20558.

Brinkmann V, Baumruker T (2006). Pulmonary and vascular pharmacology of sphingosine 1-phosphate. Curr Opin Pharmacol6: 244–250.

Chun J, Goetzl EJ, Hla T, Igarashi Y, Lynch KR, Moolenaar et al. (2002). International Union of Pharmacology. XXXIV. Lysophospholipid receptor nomenclature. Pharmacol Rev54: 265–269.

Chun J, Rosen H (2006). Lysophospholipid receptors as potential drug targets in tissue transplantation and autoimmune diseases. Curr Pharm Des12: 161–171.

Goetzl EJ, Tigyi G (2004). Lysophospholipids and their G protein-coupled receptors in biology and diseases. J Cell Biochem92: 867–868.

Ishii I, Fukushima N, Ye XQ, Chun J (2004). Lysophospholipid receptors: Signaling and biology. Annu Rev Biochem73: 321–354.

Meyer Zu Heringdorf D, Jakobs KH (2007). Lysophospholipid receptors: signalling, pharmacology and regulation by lysophospholipid metabolism. Biochim Biophys Acta1768: 923–940.

Milstien S, Gude D, Spiegel S (2007). Sphingosine 1-phosphate in neural signalling and function. Acta Paediatr Suppl96: 40–43.

Ogretmen B, Hannun YA (2004). Biologically active sphingolipids in cancer pathogenesis and treatment. Nat Rev Cancer4: 604–616.

Rosen H, Goetzl EJ (2005). Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nat Rev Immunol5: 560–570.

Rosen H, Sanna MG, Cahalan SM, Gonzalez-Cabrera PJ (2007). Tipping the gatekeeper: S1P regulation of endothelial barrier function. Trends Immunol28: 102–107.

Yatomi Y (2006). Sphingosine 1-phosphate in vascular biology: possible therapeutic strategies to control vascular diseases. Curr Pharm Des12: 575–587.

References

Albert R et al. (2005). J Med Chem48: 5373–5377.

Brinkmann V et al. (2002). J Biol Chem277: 21453–21457.

Mandala S et al. (2002). Science296: 346–349.

Okamoto H et al. (1998). J Biol Chem273: 27104–27110.

Osada M et al. (2002). Biochem Biophys Res Commun299: 483–487.

Sanna MG et al. (2004). J Biol Chem279: 13839–13848.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Tachykinin

Overview: Tachykinin receptors (provisional nomenclature) are activated by the endogenous peptides substance P (SP), neurokinin A (NKA; previously known as substance K, neurokinin α, neuromedin L), neurokinin B (NKB; previously known as neurokinin β, neuromedin K), neuropeptide K and neuropeptide γ (N-terminally extended forms of neurokinin A). The neurokinins (A and B) are mammalian members of the tachykinin family, which includes peptides of mammalian and nonmammalian origin containing the consensus sequence: Phe-x-Gly-Leu-Met. Marked species differences in pharmacology exist for all three receptors, in particular with nonpeptide ligands.

NomenclatureNK1NK2NK3
Other namesSubstance PSubstance KNeurokinin B, neuromedin K
Ensembl IDENSG00000115353ENSG00000075073ENSG00000169836
Principal transductionGq/11Gq/11Gq/11
Rank order of potencysup>NKA>NKBNKA>NKB>>SPNKB>NKA>SP
Selective agonistsSP methylester, [Sar9, Met(O2)11]SP, [Pro9]SP, septide[β-Ala8]NKA-(4-10),[Lys5, Me-Leu9,Mle10] NKA-(4-10), GR64349Senktide, [MePhe7]NKB
Selective antagonistsAprepitant (10.7; Hale et al., 1998), SR140333 (9.5), LY303870 (9.4), CP99994 (9.3), RP67580 (7.6)GR94800 (9.6), GR159897 (9.5), MEN10627 (9.2), SR48968 (9.0), MEN11420 (8.6; Catalioto et al., 1998)SR142802 (9.2), SB223412 (9.0, Sarau et al., 1997), PD157672 (7.8)
Probes[3H]- or [125I]-SP, [3H]- or [125I]-BH-[Sar9,Met(O2)11]SP, [125I]-L703606 (0.3 nM), [18F]-SPA-RQ (Bergstrom et al., 2004)[3H]-SR48968 (0.5 nM), [3H]-GR100679, [125I]-NKA[3H]-Senktide, [125I]-[MePhe7]NKB, [3H]-SR142801 (0.13 nM)

The NK1 receptor has also been described to couple to other G proteins (Roush and Kwatra, 1998). The hexapeptide agonist septide appears to bind to an overlapping but non-identical site to SP on the NK1 receptor. There are suggestions for additional subtypes of tachykinin receptor; an orphan receptor (SwissProt P30098) with structural similarities to the NK3 receptor was found to respond to NKB when expressed in Xenopus oocytes or Chinese hamster ovary cells (Donaldson et al., 1996; Krause et al., 1997).

Abbreviations: Aprepitant, 5-[[(2R,3S]-2-[(1R)-1-[3,5-bis(trifluoromethyl) phenyl]ethoxy]-3-(4-fluorphenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (also known as Emend); CP99994, (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine; [18F]-SPA-RQ, ([[18F]-2-fluoromethoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]([2S,3S]2-phenyl-piperidin-3-yl)-amine; GR100679, cyclohexylcarbonyl-Gly-Ala-DTrp-Phe-NMe2; GR159897, (R)-1-(2-[5-fluoro-1H-indol-3-yl]ethyl)-4-methoxy-4([phenylsulfinyl]methyl)piperidine; GR64349, Lys-Asp-Ser-Phe-Val-Gly-(R-γ-lactam); GR94800,N-α-benzoyl-Ala-Ala-DTrp-Phe-DPro-Pro-Nle-NH2; L-703606,cis-2(diphenylmethyl)-N-([2-iodophenyl]-methyl)-1-azabicyclo[2.2.2]octan-3-amide; L-742694, 2(s)-([3,5-bis[trifluoromethyl]benzyl]-oxy)-3(S)-phenyl-4-([3-oxo-1,2,4-triazol-5-yl]methyl)-morpholine; LY303870, (r)-1-(N-[2-methoxybenzyl]acetylamino)-3-(1H-indol-3yl)-2-(N-[2-[4-(piperidin-1-yl)piperidin-1-yl]acetyl]amino)propane; also known as lanepitant; MEN10627,cyc(2β-5β)(Met-Asp-Trp-Phe-Dap-Leu); MEN11420,cyc(2β-5β)[Asn(2-AcNH-β-D-Glc)-Asp-Trp-Phe-Dap-Leu]; also known as nepadutant; PD157672, Boc-(s)Phe-(r)αMePheNH(CH2)7NHCONH2; RP67580,R,7αR-(1-imino-2-[2-methoxyphenyl]ethyl)-7,7-diphenyl-4-perhydroisoindolone; SB223412, (s)-(-)-N-(α-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide; SR140333, (s)-1-(2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)piperidin-3-yl]ethyl)-4-phenyl-1-azoniabicyclo(2.2.2)octane chloride; SR142801, (S)-(N)-(1-[3-(1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl)propyl]-4-phenylpiperidin-4-yl)-N-methylacetamide; SR48968, (S)-N-methyl-N-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butylbenzamide; also known as saredutant

Further Reading

Candenas L, Lecci A, Pinto FM, Patak E, Maggi CA, Pennefather JN (2005). Tachykinins and tachykinin receptors: effects in the genitourinary tract. Life Sci76: 835–862.

Hoogerwerf WA, Sarna SK (2006). Tachykinin receptors as drug targets for motility disorders. Dig Dis24: 83–90.

Page NM (2004). Hemokinins and endokinins. Cell Mol Life Sci61: 1652–1663.

Pennefather JN, Lecci A, C6andenas ML, Patak E, Pinto FM, Maggi CA (2004). Tachykinins and tachykinin receptors: a growing family. Life Sci74: 1445–1463.

Quartara L, Altamura M (2006). Tachykinin receptors antagonists: from research to clinic. Curr Drug Targets7: 975–992.

References

Bergstrom M et al. (2004). Biol Psychiatry55: 1007–1012.

Catalioto RM et al. (1998). Br J Pharmacol123: 81–91.

Donaldson LF et al. (1996). Biochem J320: 1–5.

Hale JJ et al. (1998). J Med Chem41: 4607–4614.

Krause JE et al. (1997). Proc Natl Acad Sci USA94: 310–315.

Roush ED, Kwatra MM (1998). FEBS Lett428: 291–294.

Sarau HM et al. (1997). J Pharmacol Exp Ther281: 1303–1311.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Trace amine-associated

Overview: Trace amine-associated receptors (provisional nomenclature) were initially discovered as a result of a search for novel 5-HT receptors (Borowsky et al., 2001), where 15 mammalian orthologues were identified and divided into two families.

NomenclatureTA1TA2
Other namesTAA1, TaR-1, BO111TAA2, GPR58
Ensembl IDENSG00000146399ENSG00000146378
Principal transductionGsGs
Potency orderTyramine≥PEA>octopamine=dopamine (Borowsky et al., 2001)PEA>tryptamine (Borowsky et al., 2001)
Probes[3H]-Tyramine (20 nM, Borowsky et al., 2001)

TAA3 (BO107) and TAA4 are pseudogenes. The signalling characteristics and pharmacology of TAA5 (PNR, Putative Neurotransmitter Receptor, ENSG00000135569), TAA6 (Trace amine receptor 4, TaR-4, ENSG00000146383), TAA8 (Trace amine receptor 5, GPR102, ENSG00000146385) and TAA9 (trace amine associated receptor 9, ENSG00000188604) are lacking.

Abbreviation: PEA, 2-phenylethylamine

Further Reading

Branchek TA, Blackburn TP (2003). Trace amine receptors as targets for novel therapeutics: legend, myth and fact. Curr Opin Pharmacol3: 90–97.

Burchett SA, Hicks TP (2006). The mysterious trace amines: protean neuromodulators of synaptic transmission in mammalian brain. Prog Neurobiol79: 223–246.

Davenport AP (2003). Peptide and trace amine orphan receptors: prospects for new therapeutic targets. Curr Opin Pharmacol3: 127–134.

Liberles SD, Buck LB (2006). A second class of chemosensory receptors in the olfactory epithelium. Nature442: 645–650.

Lindemann L, Hoener MC (2005). A renaissance in trace amines inspired by a novel GPCR family. Trends Pharmacol Sci26: 274–281.

Mercuri NB, Bernardi G (2005). The ‘magic’ of L-dopa: why is it the gold standard Parkinson's disease therapy? Trends Pharmacol Sci26: 341–344.

Sotnikova TD, Budygin EA, Jones SR, Dykstra LA, Caron MG, Gainetdinov RR (2004). Dopamine transporter-dependent and -independent actions of trace amine beta-phenylethylamine. J Neurochem91: 362–373.

Vanti WB, Muglia P, Nguyen T, Cheng R, Kennedy JL, George SR et al. (2003). Discovery of a null mutation in a human trace amine receptor gene. Genomics82: 531–536.

Zucchi R, Chiellini G, Scanlan TS, Grandy DK (2006). Trace amine-associated receptors and their ligands. Br J Pharmacol149: 967–978.

Reference

Borowsky B et al. (2001). Proc Natl Acad Sci USA98: 8966–8971.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

TRH

Overview: Thyrotropin-releasing hormone (TRH) receptors (provisional nomenclature) are activated by the endogenous tripeptide TRH (pGlu-His-ProNH2). TRH and TRH analogues fail to distinguish TRH1 and TRH2 receptors (Sun et al., 2003). [3H]-TRH is able to label both TRH1 and TRH2 receptors with Kd values of 13 and 9 nM, respectively.

NomenclatureTRH1TRH2
Other namesTRH receptor
Ensembl IDENSG00000163485ENSMUSG00000039079, ENSRNOG00000012789
Principal transductionGqGq
Selective antagonistsMidazolam (Drummond et al., 1989), chlordiazepoxide (Straub et al., 1990), diazepam

The human orthologue of the rodent TRH2 receptor has yet to be identified.

Abbreviation: MeTRH, pGlu-[Nt-methyl]His-ProNH2

Further Reading

Colson AO, Gershengorn MC (2006). Thyrotropin-releasing hormone analogs. Mini Rev Med Chem6: 221–226.

Engel S, Gershengorn MC (2007). Thyrotropin-releasing hormone and its receptors - A hypothesis for binding and receptor activation. Pharmacol Ther113: 410–419.

Garcia SI, Pirola CJ (2005). Thyrotropin-releasing hormone in cardiovascular pathophysiology. Regul Pept128: 239–246.

Lechan RM, Fekete C (2006). The TRH neuron: a hypothalamic integrator of energy metabolism. Prog Brain Res153: 209–235.

References

Drummond AH et al. (1989). Ann N Y Acad Sci553: 197–204.

Straub RE et al. (1990). Proc Natl Acad Sci USA87: 9514–9518.

Sun Y et al. (2003). J Mol Endocrinol30: 87–97.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Urotensin-II

Overviw: The urotensin-II (U-II) receptor (UT, nomenclature as agreed by NC-IUPHAR, see Foord et al., 2005, Douglas and Ohlstein, 2000a) is activated by the endogenous dodecapeptide U-II, originally isolated from the urophysis, the endocrine organ of the caudal neurosecretory system of teleost fish (Bern et al., 1985). Several structural forms of U-II exist in fish and amphibians. The Goby orthologue was used to identify U-II as the cognate ligand for the predicted receptor encoded by the rat gene gpr14 (Coulouarn et al., 1998; Liu et al., 1999; Mori et al., 1999; Nothacker et al., 1999). Human U-II (derived from ENSG00000049247), an 11-amino-acid peptid (Coulouarn et al., 1998), retains the cyclohexapeptide sequence of goby U-II that is thought to be important in ligand binding (Kinney et al., 2002; Brkovic et al., 2003). This sequence is also conserved in the deduced amino-acid sequence of rat (14 amino-acids) and mouse (14 amino-acids) U-II, although the N-terminal is more divergent from the human sequence (Coulouarn et al., 1999).

NomenclatureUT
Other namesGPR14, SENR, UR-IIR
Ensembl IDENSG00000181408
Principal transductionGq/11
Selective agonists[Pen5]U-II-(4–11), U-II-(4–11), U-II (Grieco et al., 2002), AC7954 (Lehmann et al., 2005), FL104 and analogues (Lehmann et al., 2006; 2007)
Selective antagonistsUrantide (8.3, Patacchini et al., 2003), SB706375 (7.5–8.0, Douglas et al., 2005), palosuran (pIC50 7.1, Clozel et al., 2004), SB436811 (6.7, Jin et al, 2005)
Probes[125I]-hU-II (0.24 nM, Maguire et al., 2000)

In human vasculature, human urotensin-II elicits both vasoconstrictor (pD2 9.3–10.1, Maguire et al., 2000) and vasodilator (pIC50 10.3–10.4, Stirrat et al., 2001) responses.

Abbreviations: [Pen5]U-II-(4-11], [pencillamine, β,β-dimethylcysteine]5U-II-(4-11); AC7954, 3-(4-chlorophenyl)-3-(2-dimethyl-aminoethyl) isochroman-1-one HCl; FL104, (+)N-(1-[4-chlorophenyl]-3-dimethylaminopropyl)-4-phenylbenzamide oxalate; palosuran, 1-[2-(4-bnzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-ureasulphate,also known as ACT058362; SB436811|SB706375, 2-bromo-4,5-dimethoxy-N-[3-(R)-1-methyl-pyrrolidin-3-yloxy)-4-trifluromethyl-phenyl]-benzenesulphonamide HCl; urantide, [Pen5,DTrp7, Orn8]hU-II(4-11)

Further Reading

Ashton N (2006). Renal and vascular actions of urotensin II. Kidney Int70: 624–629.

Balment RJ, Song W, Ashton N (2005). Urotensin II: ancient hormone with new functions in vertebrate body fluid regulation. Ann N Y Acad Sci1040: 66–73.

Boos CJ, Lip GY (2006). Urotensin and cardiovascular risk among patients with end-stage renal disease: fact or fiction? Am J Hypertens19: 511–512.

Bousette N, Giaid A (2006). Urotensin-II and cardiovascular diseases. Curr Hypertens Rep8: 479–483.

Carotenuto A, Grieco P, Rovero P, Novellino E (2006). Urotensin-II receptor antagonists. Curr Med Chem13: 267–275.

Douglas SA, Ohlstein EH (2000). Urotensin receptors. (ed. Girdlestone, D) In: The IUPHAR Receptor Compendium of Receptor Characterization and Classification. pp 365–372. IUPHAR Media Ltd: London.

Douglas SA, Dhanak D, Johns DG (2004). From ‘gills to pills’: urotensin-II as a regulator of mammalian cardiorenal function. Trends Pharmacol Sci25: 76–85.

Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP et al. (2005). International Union of Pharmacology XLVI. G Protein-coupled receptor list. Pharmacol Rev57: 279–288.

Gilbert RE, Douglas SA, Krum H (2004). Urotensin-II as a novel therapeutic target in the clinical management of cardiorenal disease. Curr Opin Investig Drugs5: 276–282.

Kemp W, Roberts S, Krum H (2005). Urotensin II: a vascular mediator in health and disease. Curr Vasc Pharmacol3: 159–168.

Le Mevel JC, Mimassi N, Lancien F, Mabin D, Conlon JM (2006). Cardiovascular actions of the stress-related neurohormonal peptides, corticotropin-releasing factor and urotensin-I in the trout Oncorhynchus mykiss. Gen Comp Endocrinol146: 56–61.

Nothacker HP, Clark S (2005). From heart to mind. The urotensin II system and its evolving neurophysiological role. FEBS J272: 5694–5702.

Ong KL, Lam KS, Cheung BM (2005). Urotensin II: its function in health and its role in disease. Cardiovasc Drugs Ther19: 65–75.

Watanabe T, Kanome T, Miyazaki A, Katagiri T (2006). Human urotensin II as a link between hypertension and coronary artery disease. Hypertens Res29: 375–387.

Zhu YC, Zhu YZ, Moore PK (2006). The role of urotensin II in cardiovascular and renal physiology and diseases. Br J Pharmacol148: 884–901.

References

Bern HA et al. (1985). Recent Prog Horm Res41: 533–552.

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Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Vasopressin & oxytocin

Overview: Vasopressin (AVP) and oxytocin (OT) receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on vasopressin and oxytoxcin receptors) are activated by the endogenous cyclic nonapeptides AVP and OT. These peptides are derived from precursors (ENSG00000101200 and ENSG00000101405, respectively), which also produce neurophysins.

NomenclatureV1aV1bV2OT
Ensembl IDENSG00000166148P47901ENSG00000126895ENSG00000180914
Principal transductionGq/11Gq/11GsGq/11, G1/0
Rank order of potencyAVP>OTAVP>OTAVP>OTOT≥AVP
Selective agonistsF180, [Phe2,Orn8]VTd[D-3-Pal2]VP, d(Cha4]AVP (Derick et al., 2002), d[Leu4,Lys8]VP (Pena et al., 2007)d[Val4,DArg8]VP, OPC51803, VNA932[Thr4,Gly7]OT (Elands et al., 1988)
Selective antagonistsd(CH2)5[Tyr(Me)2, Arg8]VP, (9.0), SR49059 (8.9), YM087 (8.2)SSR149415 (8.4; Griebel et al., 2002; Serradeil-Le Gal et al., 2002)VPA985 (8.9, Albright et al., 1998), d(CH2)5[D-Ile2, Ile4]AVP (8.4), SR121463A (8.4; Serradeil-Le Gal et al., 1996), OPC31260 (7.6; Yamamura et al., 1992), YM087 (8.96)SSR126768A (9.3; Serradeil-Le Gal et al., 2004), desGlyNH2, d(CH2)5[Tyr(Me)2, Thr4, Orn8], OT (8.5), L372662 (8.4)
Probes[3 H]-AVP, [3 H]-SR49059 (1.5 nM), [3 H]-d(CH2)5[Tyr(Me)2, Arg8]AVP (1.1 nM), [125I]-HO-Phaa,D-Tyr(Me)-, Phe-Gln-Asn-Arg-Pro-Arg-NH2 (50 pM)[3 H]-AVP, [3 H]-SSR149415 (1 nM; Serradeil-Le Gal et al. 2007)[3H]-AVP, [3H]-desGly-NH2[D-Ile2,Ile4]AVP (2.8 nM), [3H]-d[D-Arg8]AVP (0.8 nM), [3 H]-SR121463A (4.1 nM)[3 H]-OT, [35S]-Non Peptide OT, Antagonist (42 pM; Lemaire et al., 2002), [125I]-d(CH2)5[Tyr(Me)2, Thr4,Orn8, Tyr-NH29]OVT (90 pM), [111In]-DOTA-dLVT (4.5 nM; Chini et al., 2003)

The V2 receptor exhibits marked species differences, such that many ligands (d(CH2)5[D-Ile2,Ile4]VP and [3H]-desGly-NH2[D-Ile2,Ile4]VP) exhibit low affinity at human V2 receptors (Ala et al., 1997). Similarly, [3H]-d[D-Arg8]VP is V2 selective in the rat, not in the human (Saito et al., 1997). The gene encoding the V2 receptor is polymorphic in man, underlying nephrogenic diabetes insipidus (Bichet, 1998). YM087 display high affinity for both human V1a and V2 receptors (Tahara et al., 1998). d[Cha4]AVP is selective only for the human and bovine V1b receptors (Derick et al., 2002), while d[Leu4,Lys8]VP has high affinity for the rat V1b receptor (Pena et al., 2007).

Abbreviations: F180, Hmp-Phe-Ile-Hgn-Asn-Cys-Pro-Dab(Abu)-Gly-NH2; [111In]-DOTA-dLVT, [111In]-DOTA-Lys8-deamino-vasotocin; L372662, 1-(1-{4-[1-(2-methyl-1-oxidopyridin-3-ylmethyl)piperidin-4-yloxyl]-2-methoxybenzoyl}piperidin-4-yl)-1,4-dihydrobenz[d][1, 3]]oxazin-2one; OPC31260, 5-dimethylamino-1-(4-[2-methylbenzoylamino]benzoyl)-2,3,4,5-tetrahydro-1H-1H-benzazepine; OPC51803, (5r)-2-(1-[2-chloro-4-{1-pyrrolidinyl}benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl)-N-isopropylacetamide; [35S]-non-peptide OT antagonist, [35S]-(1-(1-(2-(2,2,2-trifluoroethoxy)-4-(1-methylsulfonyl-4-piperidinyloxy)phenylacetyl)-4-piperidinyl)-3,4-dihydro-2(1H)-quinolinone); SR121463A, 1-(4-Boc-2-methoxybenzenesulfonyl)-5-ethoxy-3-spiro-(4-[2-morpholinoethoxy]cyclohexane)indol-2-one fumarate; equatorial isomer; SR49059, (2s)-1-2([2r3s]-[5-chloro-3-{chlorophenyl}-1-{3,4-dimethoxysulfonyl}-3-hydroxy]-2,3-dihydro-1H-indole-2-carbonyl)-pyrrolidine-2-pyroolidine carboxamide; SSR126768A, 4-chloro-3-[(3R)-(+)-5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2,3-dihydro-1H-indol-3-yl]-N-ethyl-N-(3-pyridylmethyl)-benzamide, hydro-chloride; VNA932, (2-chloro-4-[3-methyl-pyerazol-1-yl]-phenyl)-(5H,11H)-pyrrolo(2,1-c)(1,4)bnzodiazepin-10-yl-methanone; VPA985, 5-fluoro-2-methyl-N-(4-[5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl]-3-chlorophenyl)benzamide; YM087, (4′-methyl-1,4,5,6-tetrahydroimidazo [4,5-d][1]bnzazepin-6-yl) carbonyl]-2-phenylbenzanilide monohydrochloride)

Further Reading

Akerlund M (2006). Targeting the oxytocin receptor to relax the myometrium. Expert Opin Ther Targets10: 423–427.

Ali F, Guglin M, Vaitkevicius P, Ghali JK (2007). Therapeutic potential of vasopressin receptor antagonists. Drugs67: 847–858.

Arai Y, Fujimori A, Sudoh K, Sasamata M (2007). Vasopressin receptor antagonists: potential indications and clinical results. Curr Opin Pharmacol7: 124–129.

Arthur P, Taggart MJ, Mitchell BF (2007). Oxytocin and parturition: a role for increased mycometrial calcium and calcium sensitization? Front Biosci12: 619–633.

Carter CS (2007). Sex differences in oxytocin and vasopressin: implications for autism spectrum disorders? Behav Brain Res176: 170–186.

Kiss A, Mikkelsen JD (2005). Oxytocin-anatomy and functional assignments: a minireview. Endocr Regul39: 97–105.

Lemmens-Gruber R, Kamyar M (2006). Vasopressin antagonists. Cell Mol Life Sci63: 1766–1779.

Rossi J, Orlandi C, Gheorghiade M (2007). Vasopressin antagonists in the management of heart failure. Expert Rev Cardiovasc Ther5: 323–330.

Sanghi P, Uretsky BF, Schwarz ER (2005). Vasopressin antagonism: a future treatment option in heart failure. Eur Heart J26: 538–543.

Streefkerk JO, Van Zwieten PA (2006). Vasopressin receptor antagonists: pharmacological tools and potential therapeutic agents. Auton Autacoid Pharmacol26: 141–148.

Tang WH, Bhavnani S, Francis GS (2005). Vasopressin receptor antagonists in the management of acute heart failure. Expert Opin Investig Drugs14: 593–600.

References

Ala Y et al. (1997). Eur J Pharmacol331: 285–293.

Albright JD et al. (1998). J Med Chem41: 2442–2444.

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Derick S et al. (2002). Endocrinology143: 4655–4664.

Elands J et al. (1988). Am J Physiol -Endocrinol Metab254: E31–E38.

Griebel G et al. (2002). Proc Natl Acad Sci USA99: 6370–6375.

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Pena A et al. (2007). Endocrinology148: 4136–4146.

Saito M et al. (1997). Biochem Pharmacol53: 1711–1717.

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Serradeil-Le Gal C et al. (2002). J Pharmacol Exp Ther300: 1122–1130.

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Yamamura Y et al. (1992). Br J Pharmacol105: 787–791.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

VIP & PACAP

Overview: Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) receptors (nomenclature recommended by the NC-IUPHAR Subcommittee on Vasoactive Intestinal Peptide Receptors, Harmar et al., 1998) are activated by the endogenous peptides VIP, PACAP1–38, PACAP1–27, peptide histidine isoleucineamide (PHI), peptide histidine methionineamide (PHM), peptide histidine valine and growth hormone-releasing factor (GRF). PACAP type II receptors have been defined as those for which PACAP and VIP display comparable affinity. Both VPAC1 and VPAC2 meet this definition. [Arg16]chicken secretin is an agonist at both VPAC1 and secretin receptors, but can be used as an agonist at VPAC1 receptors in tissues that do not express secretin receptors (Gourlet et al., 1997a). PACAP6–38 also shows significant affinity for VPAC2 receptors. Helodermin discriminates VPAC1 and VPAC2 in a species-dependent manner (Gourlet et al., 1998).

NomenclatureVPAC1VPAC2PAC1
Other namesVIP1/PACAP, VIP, VIP1, PACAP type II, PVR2VIP2/PACAP, VIP2, PACAP3, PVR2PACAP, PACAP type I, PVR1
Ensembl IDENSG00000114812EENSG00000106018ENSG0000078549
Principal transductionGsGsGs
Rank ordr of potency Selective agonistsVIP, PACAP-(1-27) = PACAP-(1-38)> GRF > > PHI> > secretin [Arg16]chicken secretin, [Lys15,Arg,16,Leu27] VIP-(1-7)-GRF-(8-27)-NH2VIP, PACAP-(1-38)> PACAP - (1-27)> PHI > > GRF, secertin Ro251553 (Gourlet et al., 1997a, 1997b), Ro251392 (Xia et al., 1997)PACAP-(1-27), PACAP-(1-38) > > VIP > PHI Maxadilan (Moro and Lerner, 1997)
Seelective antagonists[Ac-His1,D-Phe2,Lys15, Arg16]VIP-(3-7)-GRF-(8-27)-NH2 (Gourlet et al. 1997a)PACAP-(6-38)
Probes[125I]-VIP, [125I]-PACAP[125I]-VIP, [125I]-PACAP[125I]-PACAP

Subtypes of PAC1 receptors have been proposed based on tissue differences in the potencies of PACAP1-27 and PACAP1-38; these might result from differences in G-protein coupling and second messenger mechanisms (Van Ramplebergh et al., 1996), or from alternative splicing of PAC1 receptor mRNA (Spengler et al., 1993).

Abbreviations: Ro251392, Ac-His1[Glu8,OCH3-Tyr10,Lys12, Nle17,Ala19,Asp25,Leu26,Lys27,28]VIP (cyclo 21-25); Ro251553, Ac-His1[Glu8,Lys12,N-le17,Ala19,Asp25,Lys27,28,Gly29,30, Thr31]VIP-NH2 (cyclo 21-25)

Further Reading

Abad C, Gomariz RP, Waschek JA (2006). Neuropeptide mimetics and antagonists in the treatment of inflammatory disease: focus on VIP and PACP. Curr Top Med Chem6: 151–163.

Delgado M, Pozo D, Ganea D (2004). The significance of vasoactive intestinal peptide in immunomodulation. Pharmacol Rev56: 249–290.

Gonzalez-Reey E, Varela N, Chorny A, Delgado M (2007). Therapeutical approaches of vasoactive intestinal peptide as a pleiotropic immunomodulator. Curr Pharm Des13: 1113–1139.

Groneberg DA, Rabe KF, Fischer A (2006). Novel concepts of neuropeptide-based drug therapy: vasoactive intestinal polypeptide and its receptors. Eur J Pharmacol533: 182–194.

Harmar AJ, Arimura A, Gozes I, Journot L, Laburthe M, Pisegna JR et al. (1998). International Union of Pharmacology. XVIII. Nomenclature of receptors for vasoactive intestinal peptide and pituitary adenylatee cyclase-activating polypeptide. Pharmacol Rev50: 265–270.

Hill JM (2007). Vasoactive intestinal peptide in neurodevelopmental disorders: therapeutic potential. Curr Pharm Des13: 1079–1089.

Nakata M, Yada T (2007). PACAP in the glucose and energy homeostasis: physiological role and therapeutic potential. Curr Pharm Des13: 1105–1112.

References

Gourlet P et al. (1997a). Peptides18: 1539–1545.

Gourlet P et al. (1997b). Peptides18: 403–408.

Gourlet P et al. (1998). Ann N Y Acad Sci865: 247–252.

Moro O, Lerner EA (1997). J Biol Chem272: 966–970.

Spengler D et al. (1993). Nature365: 170–175.

Van Ramplebergh J et al. (1996). Mol Pharmacol50: 1596–1604.

Xia M et al. (1997). J Pharmacol Exp Ther281: 629–633.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

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