The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors

Authors


Abstract

The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13348/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates.

Conflict of interest

The authors state that there are no conflicts of interest to declare.

Overview

G protein-coupled receptors (GPCRs) are the largest class of membrane proteins in the human genome. The term "7TM receptor" is commonly used interchangeably with "GPCR", although there are some receptors with seven transmembrane domains that do not signal through G proteins. GPCRs share a common architecture, each consisting of a single polypeptide with an extracellular N-terminus, an intracellular C-terminus and seven hydrophobic transmembrane domains (TM1-TM7) linked by three extracellular loops (ECL1-ECL3) and three intracellular loops (ICL1-ICL3). About 800 GPCRs have been identified in man, of which about half have sensory functions, mediating olfaction ( 400), taste (33), light perception (10) and pheromone signalling (5) [1309]. The remaining  350 non-sensory GPCRs mediate intersignalling by ligands that range in size from small molecules to peptide to large proteins; they are the targets for the majority of drugs in clinical usage [1451, 1560], although only a minority of these receptors are exploited therapeutically. The first classification scheme to be proposed for GPCRs [984] divided them, on the basic of sequence homology, into six classes. These classes and their prototype members were as follows: Class A(rhodopsin-like), Class B (secretin receptor family), Class C (metabotropic glutamate), Class D(fungal mating pheromone receptors), Class E (cyclic AMP receptors) and Class F (frizzled/smoothened). Of these, classes D and E are not found in vertebrates. An alternative classification scheme "GRAFS" [1666] divides vertebrate GPCRs into five classes, overlapping with the A-F nomenclature, viz:

Glutamate family (class C), which includes metabotropic glutamate receptors, a calcium-sensing receptor and GABAB receptors, as well as three taste type 1 receptors [class C list] and a family of pheromone receptors (V2 receptors) that are abundant in rodents but absent in man [1309].

Rhodopsin family (class A), which includes receptors for a wide variety of small molecules, neurotransmitters, peptides and hormones, together with olfactory receptors, visual pigments, taste type 2 receptors and five pheromone receptors (V1 receptors). [Class A list]

Adhesion family GPCRs are phylogenetically related to class B receptors, from which they differ by possessing large extracellular N-termini that are autoproteolytically cleaved from their 7TM domains at a conserved "GPCR proteolysis site" (GPS) which lies within a much larger ( 320 residue) "GPCR autoproteolysis-inducing" (GAIN) domain, an evolutionary ancient mofif also found in polycystic kidney disease 1 (PKD1)-like proteins, which has been suggested to be both required and sufficient for autoproteolysis [1538]. [Adhesion family list].

Frizzled family (class F) consists of 10 Frizzled proteins (FZD(1-10)) and Smoothened (SMO). [Frizzled family list]. The FZDs are activated by secreted lipoglycoproteins of the WNT family, whereas SMO is indirectly activated by the Hedgehog (HH) family of proteins acting on the transmembrane protein Patched (PTCH).

Secretin family (class B), encoded by 15 genes in humans. The ligands for receptors in this family are polypeptide hormones of 27-141 amino-acid residues; nine of the mammalian receptors respond to ligands that are structurally related to one another (glucagon, glucagon-like peptides (GLP-1, GLP-2), glucose-dependent insulinotropic polypeptide (GIP), secretin, vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP) and growth-hormone-releasing hormone (GHRH) [703].

GPCR families

FamilyClass AClass B (Secretin)Class C (Glutamate)AdhesionFrizzled
Receptors with known ligands197a1512011
Orphans87 (54)a-8 (1)a26 (6)a0
Sensory (olfaction)390b,c----
Sensory (vision)10d opsins----
Sensory (taste)30c taste 2-3c taste 1--
Sensory (pheromone)5c vomeronasal 1----
Total71915223311

aNumbers in brackets refer to orphan receptors for which an endogenous ligand has been proposed in at least one publication, see [396]; b[1443]; c[1309]; d[1866].

Much of our current understanding of the structure and function of GPCRs is the result of pioneering work on the visual pigment rhodopsin and on the β2 adrenoceptor, the latter culminating in the award of the 2012 Nobel Prize in chemistry to Robert Lefkowitz and Brian Kobilka [975, 1073].

Family structure

5746 Orphan and other 7TM receptors

5746 Class A Orphans

5756 Class C Orphans

5756 Taste 1 receptors

5757 Taste 2 receptors

5758 Other 7TM proteins

5759 5-Hydroxytryptamine receptors

5764 Acetylcholine receptors (muscarinic)

5766 Adenosine receptors

5768 Adhesion Class GPCRs

5770 Adrenoceptors

5774 Angiotensin receptors

5775 Apelin receptor

5777 Bile acid receptor

5778 Bombesin receptors

5780 Bradykinin receptors

5781 Calcitonin receptors

5783 Calcium-sensing receptors

5784 Cannabinoid receptors

5785 Chemerin receptor

5785 Chemokine receptors

5791 Cholecystokinin receptors

5792 Class Frizzled GPCRs

5793 Complement peptide receptors

5795 Corticotropin-releasing factor receptors

5796 Dopamine receptors

5798 Endothelin receptors

5799 G protein-coupled estrogen receptor

5800 Formylpeptide receptors

5801 Free fatty acid receptors

5803 GABAB receptors

5805 Galanin receptors

5806 Ghrelin receptor

5807 Glucagon receptor family

5809 Glycoprotein hormone receptors

5810 Gonadotrophin-releasing hormone receptors

5811 GPR18, GPR55 and GPR119

5812 Histamine receptors

5814 Hydroxycarboxylic acid receptors

5815 Kisspeptin receptor

5816 Leukotriene receptors

5818 Lysophospholipid (LPA) receptors

5819 Lysophospholipid (S1P) receptors

5820 Melanin-concentrating hormone receptors

5821 Melanocortin receptors

5822 Melatonin receptors

5823 Metabotropic glutamate receptors

5826 Motilin receptor

5827 Neuromedin U receptors

5828 Neuropeptide FF/neuropeptide AF receptors

5829 Neuropeptide S receptor

5829 Neuropeptide W/neuropeptide B receptors

5830 Neuropeptide Y receptors

5832 Neurotensin receptors

5833 Opioid receptors

5835 Orexin receptors

5836 Oxoglutarate receptor

5836 P2Y receptors

5838 Parathyroid hormone receptors

5839 Platelet-activating factor receptor

5840 Prokineticin receptors

5841 Prolactin-releasing peptide receptor

5842 Prostanoid receptors

5844 Proteinase-activated receptors

5846 QRFP receptor

5846 Relaxin family peptide receptors

5848 Somatostatin receptors

5850 Succinate receptor

5850 Tachykinin receptors

5852 Thyrotropin-releasing hormone receptors

5852 Trace amine receptor

5854 Urotensin receptor

5854 Vasopressin and oxytocin receptors

5856 VIP and PACAP receptors

Orphan and other 7TM receptors

Class A Orphans

Overview

Table 1 lists a number of putative GPCRs identified by NC-IUPHAR[530], for which preliminary evidence for an endogenous ligand has been published, or for which there exists a potential link to a disease, or disorder. These GPCRs have recently been reviewed in detail [396]. The GPCRs in Table 1 are all Class A, rhodopsin-like GPCRs. Class A orphan GPCRs not listed in Table 1 are putative GPCRs with as-yet unidentified endogenous ligands.

Table 1. Class A orphan GPCRs with putative endogenous ligands
GPR1GPR3GPR4GPR6GPR12GPR15GPR17GPR20
GPR22GPR26GPR31GPR34GPR35GPR37GPR39GPR50
GPR63GRP65GPR68GPR75GPR84GPR87GPR88GPR132
GPR149GPR161GPR183LGR4LGR5LGR6MAS1MRGPRD
MRGPRX1MRGPRX2P2RY10TAAR2    

In addition the orphan receptors GPR18, GPR55 and GPR119 which are reported to respond to endogenous agents analogous to the endogenous cannabinoid ligands have been grouped together (GPR18, GPR55 and GPR119).

NomenclatureGPR1GPR3GPR4GPR6
HGNC, UniProtGPR1, P46091GPR3, P46089GPR4, P46093GPR6, P46095
Endogenous ligandProtons
Endogenous agonistschemerin (RARRES2, Q99969) (pKd 8.3) [95]
Agonistsdiphenyleneiodonium chloride (pEC50 6) [2091]
CommentsReported to act as a co-receptor for HIV [1724]. See review [396] for discussion of pairing with chemerin.sphingosine 1-phosphate was reported to be an endogenous agonist [1921], but this finding was not replicated in subsequent studies [2093]. Reported to activate adenylyl cyclase constitutively through Gs [466]. Gene disruption results in premature ovarian ageing [1063], reduced β-amyloid deposition [1868] and hypersensitivity to thermal pain [1615] in mice. First small molecule inverse agonist [860] and agonists identified [2091].An initial report suggesting activation by lysophosphatidylcholine and sphingosylphosphorylcholine [2131] has been retracted [2148]. GPR4, GPR65, GPR68 and GPR132 are now thought to function as proton-sensing receptors detecting acidic pH [396, 1704]. Gene disruption is associated with increased perinatal mortality and impaired vascular proliferation [2085]. Negative allosteric modulators of GPR4 have been reported [1889].An initial report that sphingosine 1-phosphate (S1P) was a high-affinity ligand (EC50 value of 39nM) [815, 1921] was not repeated by arrestin PathHunter[TM] assays [1785, 2093]. Reported to activate adenylyl cyclase constitutively through Gs and to be located intracellularly [1453]. GPR6-deficient mice showed reduced striatal cyclic AMP production in vitro and selected alterations in instrumental conditioning in vivo. [1134].
NomenclatureGPR12GPR15GPR17GPR19
HGNC, UniProtGPR12, P47775GPR15, P49685GPR17, Q13304GPR19, Q15760
Endogenous agonistsUDP-glucose (pEC50 5.9–9.5) [130, 344], LTC4 (pEC50 7.8–9.5) [344], UDP-galactose (pEC50 6–8.9) [130, 344], uridine diphosphate (pEC50 6–8.8) [130, 344], LTD4 (pEC50 8.1–8.4) [344]
CommentsReports that sphingosine 1-phosphate is a ligand of GPR12 [814, 1921] have not been replicated in arrestin-based assays [1785, 2093]. Gene disruption results in dyslipidemia and obesity [154].Reported to act as a co-receptor for HIV [462]. In an infection-induced colitis model, Gpr15 knockout mice were more prone to tissue damage and inflammatory cytokine expression [945].Reported to be a dual leukotriene and uridine diphosphate receptor [344]. Another group instead proposed that GPR17 functions as a negative regulator of the CysLT1 receptor response to leukotriene D4 (LTD4). For further discussion, see [396]. Reported to antagonize CysLT1 receptor signalling in vivoand in vitro [1175]. See reviews [250] and [396].
NomenclatureGPR20GPR21GPR22GPR25GPR26
HGNC, UniProtGPR20, Q99678GPR21, Q99679GPR22, Q99680GPR25, O00155GPR26, Q8NDV2
CommentsReported to inhibit adenylyl cyclase constitutively through Gi/o [708]. GPR20 deficient mice exhibit hyperactivity characterised by increased total distance travelled in an open field test [207].Gpr21 knockout mice were resistant to diet-induced obesity, exhibiting an increase in glucose tolerance and insulin sensitivity, as well as a modest lean phenotype [1448].Gene disruption results in increased severity of functional decompensation following aortic banding [10]. Identified as a susceptibility locus for osteoarthritis [494, 929, 1935].Has been reported to activate adenylyl cyclase constitutively through Gs [880]. Gpr26 knockout mice show increased levels of anxiety and depression-like behaviours [2117].
NomenclatureGPR27GPR31GPR32GPR33GPR34
HGNC, UniProtGPR27, Q9NS67GPR31, O00270GPR32, O75388GPR33, Q49SQ1GPR34, Q9UPC5
Rank order of potencyresolvin D1>LXA4
Endogenous agonists12S-HETE (Selective) (pEC50 9.6) [665] – Mouseresolvin D1 (pEC50 11.1) [1006], LXA4 (pEC50 9.7) [1006]lysophosphatidylserine (Selective) (pEC50 6.6–6.9) [960, 1817]
Labelled ligands[3H]resolvin D1 (Agonist) (pKd 9.7) [1006]
CommentsKnockdown of Gpr27 reduces endogenous mouse insulin promotor activity and glucose-stimulated insulin secretion [1012].See [396] for discussion of pairing.resolvin D1 has been demonstrated to activate GPR32 in two publications [316, 1006]. The pairing was not replicated in a recent study based on arrestin recruitment [1785]. GPR32 is a pseudogene in mice and rats. See reviews [250] and [396].GPR33 is a pseudogene in most individuals, containing a premature stop codon within the coding sequence of the second intracellular loop [1621].Lysophosphatidylserine has been reported to be a ligand of GPR34 in several publications, but the pairing was not replicated in a recent study based on arrestin recruitment [1785]. Fails to respond to a variety of lipid-derived agents [2093]. Gene disruption results in an enhanced immune response [1102]. Characterization of agonists at this receptor is discussed in [819] and [396].
NomenclatureGPR35GPR37GPR37L1GPR39GPR42
HGNC, UniProtGPR35, Q9HC97GPR37, O15354GPR37L1, O60883GPR39, O43194GPR42, O15529
Endogenous agonists2-oleoyl-LPA (pEC50 7.3–7.5) [1436], kynurenic acid (pEC50 3.9–4.4) [1785, 1980]Zn2+ [775]
Agonistsneuropeptide head activator (pEC50 8–8.5) [1578]compound 1 [PMID: 24900608] (pEC50 4.9–7.2) [166]
CommentsSeveral studies have shown that kynurenic acid is an agonist of GPR35 but it remains controversial whether the proposed endogenous ligand reaches sufficient tissue concentrations to activate the receptor [1015]. 2-oleoyl-LPA has also been proposed as an endogenous ligand [1436] but these results were not replicated in an arrestin assay [1785]. The phosphodiesterase inhibitor zaprinast [1863] has become widely used as a surrogate agonist to investigate GPR35 pharmacology and signalling [1863]. GPR35 is also activated by the pharmaceutical adjunct pamoic acid [2124]. See reviews [396] and [429].Reported to associate and regulate the dopamine transporter [1207] and to be a substrate for parkin [1205]. Gene disruption results in altered striatal signalling [1206]. The peptides prosaptide and prosaposin are proposed as endogenous ligands for GPR37 and GPR37L1 [1264].The peptides prosaptide and prosaposin are proposed as endogenous ligands for GPR37 and GPR37L1 [1264].Zn2+ has been reported to be a potent and efficacious agonist of human, mouse and rat GPR39 [2089]. obestatin (GHRL, Q9UBU3), a fragment from the ghrelin precursor, was reported initially as an endogenous ligand, but subsequent studies failed to reproduce these findings. GPR39 has been reported to be down-regulated in adipose tissue in obesity-related diabetes [273]. Gene disruption results in obesity and altered adipocyte metabolism [1497]. Reviewed in [396].
NomenclatureGPR45GPR50GPR52GPR61
HGNC, UniProtGPR45, Q9Y5Y3GPR50, Q13585GPR52, Q9Y2T5GPR61, Q9BZJ8
CommentsGPR50 is structurally related to MT1 and MT2 melatonin receptors, with which it heterodimerises constitutively and specifically [1089]. Gpr50 knockout mice display abnormal thermoregulation and are much more likely than wild-type mice to enter fasting-induced torpor [111].First small molecule agonist reported [1703].GPR61 deficient mice exhibit obesity associated with hyperphagia [1363]. Although no endogenous ligands have been identified, 5-(nonyloxy)tryptamine has been reported to be a low affinity inverse agonist [1852].
NomenclatureGPR62GPR63GPR65GPR68GPR75
HGNC, UniProtGPR62, Q9BZJ7GPR63, Q9BZJ6GPR65, Q8IYL9GPR68, Q15743GPR75, O95800
Endogenous ligandProtonsProtons
Commentssphingosine 1-phosphate and dioleoylphosphatidic acid have been reported to be low affinity agonists for GPR63 [1394] but this finding was not replicated in an arrestin-based assay [2093].GPR4, GPR65, GPR68 and GPR132 are now thought to function as proton-sensing receptors detecting acidic pH [396, 1704]. Reported to activate adenylyl cyclase; gene disruption leads to reduced eosinophilia in models of allergic airway disease [1000].GPR68 was previously identified as a receptor for sphingosylphosphorylcholine (SPC) [2068], but the original publication has been retracted [2067]. GPR4, GPR65, GPR68 and GPR132 are now thought to function as proton-sensing receptors detecting acidic pH [396, 1704]. A family of 3,5-disubstituted isoxazoles were identified as agonists of GPR68 [1617].CCL5 (CCL5, P13501) was reported to be an agonist of GPR75 [816], but the pairing could not be repeated in an arrestin assay [1785].
NomenclatureGPR78GPR79GPR82GPR83GPR84
HGNC, UniProtGPR78, Q96P69GPR79, –GPR82, Q96P67GPR83, Q9NYM4GPR84, Q9NQS5
AgonistsZn2+ (pEC50 5) [1351] – Mousedecanoic acid (pEC50 5–5.4) [1785, 1981], undecanoic acid (pEC50 5.1) [1981], lauric acid (pEC50 5) [1981]
CommentsGPR78 has been reported to be constitutively active, coupled to elevated cAMP production [880].Mice with Gpr82 knockout have a lower body weight and body fat content associated with reduced food intake, decreased serum triglyceride levels, as well as higher insulin sensitivity and glucose tolerance [479].One isoform has been implicated in the induction of CD4(+) CD25(+) regulatory T cells (Tregs) during inflammatory immune responses [696]. The extracellular N-terminal domain is reported as an intramolecular inverse agonist [1352].Medium chain free fatty acids with carbon chain lengths of 9-14 activate GPR84 [1828, 1981]. A surrogate ligand for GPR84, 6-n-octylaminouracil has also been proposed [1828]. See review [396] for discussion of classification. Mutational analysis and molecular modelling of GPR84 has been reported [1397].
NomenclatureGPR85GPR87GPR88GPR101
HGNC, UniProtGPR85, P60893GPR87, Q9BY21GPR88, Q9GZN0GPR101, Q96P66
Endogenous agonistsLPA (pEC50 7.4) [1344, 1836]
Agonistscompound 2 [PMID: 24793972] (pEC50 6.2) [868]
CommentsProposed to regulate hippocampal neurogenesis in the adult, as well as neurogenesis-dependent learning and memory [303].Gene disruption results in altered striatal signalling [1137]. Small molecule agonists have been reported [147].Mutations in GPR101 have been linked to gigantism and acromegaly [1906].
NomenclatureGPR132GPR135GPR139GPR141GPR142
HGNC, UniProtGPR132, Q9UNW8GPR135, Q8IZ08GPR139, Q6DWJ6GPR141, Q7Z602GPR142, Q7Z601
Endogenous ligandProtons
Agonistscompound 1a [PMID: 24900311] (pEC50 7.4) [1721]
CommentsGPR4, GPR65, GPR68 and GPR132 are now thought to function as proton-sensing receptors detecting acidic pH [396, 1704]. Reported to respond to lysophosphatidylcholine [891], but later retracted [2038].Peptide agonists have been reported [828].Small molecule agonists have been reported [1890, 2106].
NomenclatureGPR146GPR148GPR149GPR150GPR151
HGNC, UniProtGPR146, Q96CH1GPR148, Q8TDV2GPR149, Q86SP6GPR150, Q8NGU9GPR151, Q8TDV0
CommentsYosten et al. demonstrated inhibition of proinsulin C-peptide (INS, P01308)-induced stimulation of cFos expression folllowing knockdown of GPR146 in KATO III cells, suggesting proinsulin C-peptide as an endogenous ligand of the receptor [2103].Gpr149 knockout mice displayed increased fertility and enhanced ovulation, with increased levels of FSH receptor and cyclin D2 mRNA levels [463].GPR151 responded to galanin with an EC50 value of 2 μM, suggesting that the endogenous ligand shares structural features with galanin (GAL, P22466) [813].
NomenclatureGPR152GPR153GPR160GPR161GPR162
HGNC, UniProtGPR152, Q8TDT2GPR153, Q6NV75GPR160, Q9UJ42GPR161, Q8N6U8GPR162, Q16538
CommentsA C-terminal truncation (deletion) mutation in Gpr161 causes congenital cataracts and neural tube defects in the vacuolated lens (vl) mouse mutant [1226]. The mutated receptor is associated with cataract, spina bifida and white belly spot phenotypes in mice [994]. Gene disruption is associated with a failure of asymmetric embryonic development in zebrafish [1085].
NomenclatureGPR171GPR173GPR174GPR176GPR182
HGNC, UniProtGPR171, O14626GPR173, Q9NS66GPR174, Q9BXC1GPR176, Q14439GPR182, O15218
Endogenous agonistslysophosphatidylserine (pEC50 7.1) [825]
CommentsGPR171 has been shown to be activated by the endogenous peptide BigLEN {Mouse}. This receptor-peptide interaction is believed to be involved in regulating feeding and metabolism responses [621].See [819] which discusses characterization of agonists at this receptor.Rat GPR182 was first proposed as the adrenomedullin receptor [904]. However, it was later reported that rat and human GPR182 did not respond to adrenomedullin [927] and GPR182 is not currently considered to be a genuine adrenomedullin receptor [722].
NomenclatureGPR183LGR4LGR5LGR6MAS1
HGNC, UniProtGPR183, P32249LGR4, Q9BXB1LGR5, O75473LGR6, Q9HBX8MAS1, P04201
Endogenous agonists7α,25-dihydroxycholesterol (Selective) (pEC50 8.1–9.8) [694, 1125], 7α,27-dihydroxycholesterol (Selective) (pEC50 8.9) [1125], 7β, 25-dihydroxycholesterol (Selective) (pEC50 8.7) [1125], 7β, 27-dihydroxycholesterol (Selective) (pEC50 7.3) [1125]R-spondin-2 (RSPO2, Q6UXX9) (pEC50 12.5) [266], R-spondin-1 (RSPO1, Q2MKA7) (pEC50 10.7) [266], R-spondin-3 (RSPO3, Q9BXY4) (pEC50 10.7) [266], R-spondin-4 (RSPO4, Q2I0M5) (pEC50 10.1) [266]R-spondin-2 (RSPO2, Q6UXX9) (pEC50 12) [266], R-spondin-1 (RSPO1, Q2MKA7) (pEC50 11.1) [266], R-spondin-3 (RSPO3, Q9BXY4) (pEC50 11) [266], R-spondin-4 (RSPO4, Q2I0M5) (pEC50 9.4) [266]R-spondin-1 (RSPO1, Q2MKA7) [266, 2140], R-spondin-2 (RSPO2, Q6UXX9) [266, 2140], R-spondin-3 (RSPO3, Q9BXY4) [266, 2140], R-spondin-4 (RSPO4, Q2I0M5) [266, 2140]
Agonistsangiotensin-(1-7) (AGT, P01019) (pKi 7.3) [612] – Mouse
CommentsTwo independent publications have shown that 7α,25-dihydroxycholesterol is an agonist of GPR183 and have demonstrated by mass spectrometry that this oxysterol is present endogenously in tissues [694, 1125]. Gpr183-deficient mice show a reduction in the early antibody response to a T-dependent antigen. GPR183-deficient B cells fail to migrate to the outer follicle and instead stay in the follicle centre [923, 1488].LGR4 does not couple to heterotrimeric G proteins or recruit arrestins when stimulated by the R-spondins, indicating a unique mechanism of action. R-spondins bind to LGR4, which specifically associates with Frizzled and LDL receptor-related proteins (LRPs) that are activated by the extracellular Wnt molecules and then trigger canonical Wnt signalling to increase gene expression [266, 1612, 2140]. Gene disruption leads to multiple developmental disorders [869, 1154, 1781, 2005].The four R-spondins can bind to LGR4, LGR5, and LGR6, which specifically associate with Frizzled and LDL receptor-related proteins (LRPs), proteins that are activated by extracellular Wnt molecules and which then trigger canonical Wnt signalling to increase gene expression [266, 2140].
NomenclatureMAS1LMRGPRDMRGPREMRGPRFMRGPRG
HGNC, UniProtMAS1L, P35410MRGPRD, Q8TDS7MRGPRE, Q86SM8MRGPRF, Q96AM1MRGPRG, Q86SM5
Endogenous agonistsβ-alanine (pEC50 4.8) [1729, 1785]
CommentsAn endogenous peptide with a high degree of sequence similarity to angiotensin-(1-7) (AGT, P01019), alamandine (AGT), was shown to promote NO release in MRGPRD-transfected cells. The binding of alamandine to MRGPRD to was shown to be blocked by D-Pro7-angiotensin-(1-7), β-alanine and PD123319 [1045]. Genetic ablation of MRGPRD+ neurons of adult mice decreased behavioural sensitivity to mechanical stimuli but not to thermal stimuli [278]. See reviews [396] and [1779].See reviews [396] and [1779].MRGPRF has been reported to respond to stimulation by angiotensin metabolites [589]. See reviews [396] and [1779].See reviews [396] and [1779].
NomenclatureMRGPRX1MRGPRX2MRGPRX3MRGPRX4
HGNC, UniProtMRGPRX1, Q96LB2MRGPRX2, Q96LB1MRGPRX3, Q96LB0MRGPRX4, Q96LA9
Endogenous agonistsbovine adrenal medulla peptide 8-22 (PENK, P01210) (Selective) (pEC50 5.3–7.8) [299, 1080, 1785]PAMP-20 (ADM, P35318) (Selective) [899]
Agonistscortistatin-14 {Mouse, Rat} (pEC50 6.9–7.6) [899, 1594, 1785]
Selective agonistsPAMP-12 (human) (pEC50 7.2–7.7) [899]
CommentsReported to mediate the sensation of itch [1131, 1739]. Reports that bovine adrenal medulla peptide 8-22 (PENK, P01210) was the most potent of a series of proenkephalin A-derived peptides as an agonist of MRGPRX1 in assays of calcium mobilisation and radioligand binding [1080] were replicated in an independent study using an arrestin recruitment assay [1785]. See reviews [396] and [1779].A diverse range of substances has been reported to be agonists of MRGPRX2, with cortistatin 14 the highest potency agonist in assays of calcium mobilisation [1594], also confirmed in an independent study using an arrestin recruitment assay [1785]. See reviews [396] and [1779].See reviews [396] and [1779].
NomenclatureOPN3OPN4OPN5P2RY8
HGNC, UniProtOPN3, Q9H1Y3OPN4, Q9UHM6OPN5, Q6U736P2RY8, Q86VZ1
CommentsEvidence indicates OPN5 triggers a UV-sensitive Gi-mediated signalling pathway in mammalian tissues [982].
NomenclatureP2RY10TAAR2TAAR3TAAR4P
HGNC, UniProtP2RY10, O00398TAAR2, Q9P1P5TAAR3, Q9P1P4TAAR4P, –
Rank order of potencyβ-phenylethylamine>tryptamine [185]
Endogenous agonistssphingosine 1-phosphate (Selective) (pEC50 7.3) [1344], LPA (Selective) (pEC50 6.9) [1344]
CommentsProbable pseudogene in 10-15% of Asians due to a polymorphism (rs8192646) producing a premature stop codon at amino acid 168 [396].TAAR3 is thought to be a pseudogene in man though functional in rodents [396].Pseudogene in man but functional in rodents [396].
NomenclatureTAAR5TAAR6TAAR8TAAR9
HGNC, UniProtTAAR5, O14804TAAR6, Q96RI8TAAR8, Q969N4TAAR9, Q96RI9
CommentsTrimethylamine is reported as an agonist [1974] and 3-iodothyronamine an inverse agonist [426].TAAR9 appears to be functional in most individuals but has a polymorphic premature stop codon at amino acid 61 (rs2842899) with an allele frequency of 10-30% in different populations [1944].

Class C Orphans

Taste 1 receptors

Overview

Whilst the taste of acid and salty foods appear to be sensed by regulation of ion channel activity, bitter, sweet and umami tastes are sensed by specialised GPCR. Two classes of taste GPCR have been identified, T1R and T2R, which are similar in sequence and structure to Class C and Class A GPCR, respectively. Activation of taste receptors appears to involve gustducin- (Gαt3) and Gα14-mediated signalling, although the precise mechanisms remain obscure. Gene disruption studies suggest the involvement of PLCβ2 [2122], TRPM5 [2122] and IP3 [764] receptors in post-receptor signalling of taste receptors. Although predominantly associated with the oral cavity, taste receptors are also located elsewhere, including further down the gastrointestinal system, in the lungs and in the brain.

Sweet/Umami

T1R3 acts as an obligate partner in T1R1/T1R3 and T1R2/T1R3 heterodimers, which sense umami or sweet, respectively. T1R1/T1R3 heterodimers respond to L-glutamic acid and may be positively allosterically modulated by 5'-nucleoside monophosphates, such as 5'-GMP[1096]. T1R2/T1R3 heterodimers respond to sugars, such as sucrose, and artificial sweeteners, such as saccharin[1376].

Taste 2 receptors

Bitter

The composition and stoichiometry of bitter taste receptors is not yet established. Bitter receptors appear to separate into two groups, with very restricted ligand specificity or much broader responsiveness. For example, T2R5 responded to cycloheximide, but not 10 other bitter compounds [287], while T2R14 responded to at least eight different bitter tastants, including (-)-α-thujone and picrotoxinin[119].

Specialist database BitterDB contains additional information on bitter compounds and receptors [2023].

Other 7TM proteins

NomenclatureGPR107GPR137OR51E1TPRA1GPR143GPR157
HGNC, UniProtGPR107, Q5VW38GPR137, Q96N19OR51E1, Q8TCB6TPRA1, Q86W33GPR143, P51810GPR157, Q5UAW9
Endogenous agonistslevodopa [1141]
CommentsGPR107 is a member of the LUSTR family of proteins found in both plants and animals, having similar topology to Gprotein-coupled receptors [461]OR51E1 is a putative olfactory receptor.TPRA1 shows no homology to known G protein-coupled receptors.Loss-of-function mutations underlie ocular albinism type 1 [103].GPR157 has ambiguous sequence similarities to several different GPCR families (class A, class B and the slime mould cyclic AMP receptor). Because of its distant relationship to other GPCRs, it cannot be readily classified.

5-Hydroxytryptamine receptors

Overview

5-HT receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on 5-HT receptors [789] and subsequently revised [707]) are, with the exception of the ionotropic 5-HT3 class, GPCR receptors where the endogenous agonist is 5-hydroxytryptamine. The diversity of metabotropic 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. Unique amongst the GPCRs, RNA editing produces 5-HT2C receptor isoforms that differ in function, such as efficiency and specificity of coupling to Gq/11 and also pharmacology [164, 2011]. Most 5-HT receptors (except 5-ht 1e and 5-ht 5a/5b) play specific roles mediating functional responses in different tissues (reviewed by [1554, 1957].

Nomenclature5-HT1A receptor5-HT1B receptor5-HT1D receptor5-ht1e receptor5-HT1F receptor
HGNC, UniProtHTR1A, P08908HTR1B, P28222HTR1D, P28221HTR1E, P28566HTR1F, P30939
AgonistsU92016A (pKi 9.7) [1240], vilazodone (Partial agonist) (pKi 9.7) [402], vortioxetine (Partial agonist) (pKi 7.8) [90]L-694,247 (pKi 9.2) [637], naratriptan (Partial agonist) (pKi 8.1) [1365], eletriptan (pKi 8) [1365], frovatriptan (pKi 8) [2069], zolmitriptan (Partial agonist) (pKi 7.7) [1365], vortioxetine (Partial agonist) (pKi 7.5) [90], rizatriptan (Partial agonist) (pKi 6.9) [1365]dihydroergotamine (pKi 9.2–9.9) [684, 1084, 1091], ergotamine (pKi 9.1) [616], L-694,247 (pKi 9) [2052], naratriptan (pKi 8.4–9) [432, 1365, 1577], zolmitriptan (pKi 8.9) [1365], frovatriptan (pKi 8.4) [2069], rizatriptan (pKi 7.9) [1365]BRL-54443 (pKi 8.7) [227]BRL-54443 (pKi 8.9) [227], eletriptan (pKi 8) [1365], sumatriptan (pKi 7.2–7.9) [11, 12, 1365, 1968]
Selective agonists8-OH-DPAT (pKi 8.4–9.4) [406, 685, 896, 1079, 1280, 1386, 1388, 1389], NLX-101 (pKi 8.6) [1387]CP94253 (pKi 8.7) [976]PNU109291 (pKi 9.1) [483] – Gorilla, eletriptan (pKi 8.9) [1365]lasmiditan (pKi 8.7) [1375], LY334370 (pKi 8.7) [1968], 5-BODMT (pKi 8.4) [966], LY344864 (pKi 8.2) [1502]
Antagonists(S)-UH 301 (pKi 7.9) [1386]
Selective antagonistsWAY-100635 (pKi 7.9–9.2) [1386, 1388], robalzotan (pKi 9.2) [872]SB 224289 (Inverse agonist) (pKi 8.2–8.6) [583, 1384, 1696], SB236057 (Inverse agonist) (pKi 8.2) [1272], GR-55562 (pKB 7.4) [791]SB 714786 (pKi 9.1) [1987]
Nomenclature5-HT1A receptor5-HT1B receptor5-HT1D receptor5-ht1e receptor5-HT1F receptor
Labelled ligands[3H]robalzotan (Antagonist) (pKd 9.8) [861], [3H]WAY100635 (Antagonist) (pKd 9.5) [933], [3H]8-OH-DPAT (Agonist) (pKd 6–9.4) [156, 896, 1385, 1388], [3H]NLX-112 (Agonist) (pKd 8.9) [748], [11C]WAY100635 (Antagonist) [1915], p-[18F]MPPF (Antagonist) [368][3H]N-methyl-AZ10419369 (Agonist, Partial agonist) (pKd 9.4) [1182], [3H]GR 125,743 (Selective Antagonist) (pKd 8.6–9.2) [637, 2061], [3H]alniditan (Agonist) (pKd 8.6–9) [1084], [125I]GTI (Agonist) (pKd 8.9) [193, 232] – Rat, [3H]eletriptan (Agonist, Partial agonist) (pKd 8.5) [1365], [3H]sumatriptan (Agonist, Partial agonist) (pKd 8) [1365], [11C]AZ10419369 (Agonist, Partial agonist) [1950][3H]eletriptan (Agonist) (pKd 9.1) [1365], [3H]alniditan (Agonist) (pKd 8.8–8.9) [1084], [125I]GTI (Selective Agonist) (pKd 8.9) [193, 232] – Rat, [3H]GR 125,743 (Selective Antagonist) (pKd 8.6) [2061], [3H]sumatriptan (Agonist) (pKd 8.2) [1365][3H]5-HT (Agonist) (pKd 8.1–8.2) [1237, 1463][3H]LY334370 (Agonist) (pKd 9.4) [1968], [125I]LSD (Agonist) (pKd 9) [44] – Mouse
CommentsWang et al. (2013) report X-ray structures which reveal the binding modality of ergotamine and dihydroergotamine to the 5-HT1B receptor in comparison with the structure of the 5-HT2B receptor [1978].
Nomenclature5-HT2A receptor5-HT2B receptor5-HT2C receptor5-HT4 receptor
HGNC, UniProtHTR2A, P28223HTR2B, P41595HTR2C, P28335HTR4, Q13639
AgonistsDOI (pKi 7.4–9.2) [204, 1374, 1755]methysergide (Partial agonist) (pKi 8–9.4) [970, 1605, 1969], DOI (pKi 7.6–7.7) [1025, 1374, 1659]DOI (pKi 7.2–8.6) [465, 1374, 1659], Ro 60-0175 (pKi 7.7–8.2) [953, 970]cisapride (Partial agonist) (pKi 6.4–7.4) [77, 128, 597, 1266, 1267, 1941]
Selective agonistsBW723C86 (pKi 7.3–8.6) [108, 970, 1659], Ro 60-0175 (pKi 8.3) [970]WAY-163909 (pKi 6.7–8) [454], lorcaserin (pKi 7.8) [1878]TD-8954 (pKi 9.4) [1250], ML 10302 (Partial agonist) (pKi 7.9–9) [136, 160, 1266, 1267, 1268], RS67506 (pEC50 8.8) [731] – Rat, relenopride (Partial agonist) (pKi 8.3) [607], velusetrag (pKi 7.7) [1139, 1763], BIMU 8 (pKi 7.3) [347]
Antagonistsrisperidone (Inverse agonist) (pKi 9.3–10) [986, 1008, 1675], mianserin (pKi 7.7–9.6) [970, 1001, 1280], ziprasidone (pKi 8.8–9.5) [986, 1008, 1675, 1711], volinanserin (pIC50 6.5–9.3) [970, 1142, 1568], blonanserin (pKi 9.1) [1421], clozapine (Inverse agonist) (pKi 7.6–9) [970, 1008, 1277, 1675, 1943], olanzapine (pKi 8.6–8.9) [986, 1008, 1675, 1711], nefazodone (pKi 8.2) [1698], chlorpromazine (Inverse agonist) (pKi 8.1) [1008], loxapine (Inverse agonist) (pKi 8.1) [1008], trifluoperazine (pKi 7.9) [1008], pimozide (pKi 7.1–7.7) [986, 1008], trazodone (pKi 7.4) [970], haloperidol (pKi 6.7–7.3) [1008, 1277, 1675, 1711, 1943], mesoridazine (pKi 7.3) [326], mirtazapine (pKi 7.2) [513], mirtazapine (pKi 7.2) [513], quetiapine (pKi 6.4–7) [986, 1008], molindone (pKi 6.5) [1008]mianserin (pKi 7.9–8.8) [180, 970, 1969]mianserin (Inverse agonist) (pKi 8.3–9.2) [524, 970, 1280], methysergide (pKi 8.6–9.1) [465, 970], ziprasidone (Inverse agonist) (pKi 7.9–9) [743, 1008, 1711], olanzapine (Inverse agonist) (pKi 8.1–8.4) [743, 1008, 1711], loxapine (Inverse agonist) (pKi 7.8–8) [743, 1008], mirtazapine (pKi 7.4) [513], mirtazapine (pKi 7.4) [513], trazodone (pKi 6.6) [970], trifluoperazine (pKi 6.4) [1008], agomelatine (pKi 6.2) [1276]
Selective antagonistsketanserin (pKi 8.1–9.7) [234, 970, 1559], pimavanserin (Inverse agonist) (pKi 9.3) [572, 1943]BF-1 (pKi 10.1) [1671], RS-127445 (pKi 9–9.5) [180, 970], EGIS-7625 (pKi 9) [1001]FR260010 (pKi 9) [700], SB 242084 (pKi 8.2–9) [928, 970], RS-102221 (pKi 8.3–8.4) [181, 970]RS 100235 (pKi 8.7–12.2) [347, 1589], SB 204070 (pKi 9.8–10.4) [128, 1266, 1267, 1941], GR 113808 (pKi 9.3–10.3) [77, 128, 160, 347, 1267, 1589, 1941]
Labelled ligands[3H]fananserin (Antagonist) (pKd 9.9) [1188] – Rat, [3H]ketanserin (Antagonist) (pKd 8.6–9.7) [970, 1559], [11C]volinanserin (Antagonist) [676], [18F]altanserin (Antagonist) [1601][3H]LSD (Agonist) (pKd 8.7) [1559], [3H]5-HT (Agonist) (pKd 8.1) [1967] – Rat, [3H]mesulergine (Antagonist, Inverse agonist) (pKd 7.9) [970], [125I]DOI (Agonist) (pKd 7.7–7.6)[125I]DOI (Agonist) (pKd 8.7–9) [524], [3H]mesulergine (Antagonist, Inverse agonist) (pKd 9.3–8.7) [524, 1559], [3H]LSD (Agonist)[123I]SB 207710 (Antagonist) (pKd 10.1) [228] – Pig, [3H]GR 113808 (Antagonist) (pKd 10.3–9.7) [77, 128, 1268, 1941], [3H]RS 57639 (Selective Antagonist) (pKd 9.7) [179] – Guinea pig, [11C]SB207145 (Antagonist) (pKd 8.6) [1169]
CommentsLSD (lysergic acid) and ergotamine show a strong preference for arrestin recruitment over G protein coupling at the 5-HT2B receptor, with no such preference evident at 5-HT1B receptors, and they also antagonise 5-HT7A receptors [1963]. DHE (dihydroergocryptine), pergolide and cabergoline also show significant preference for arrestin recruitment over G protein coupling at 5-HT2B receptors [1963].The serotonin antagonist mesulergine was key to the discovery of the 5-HT2C receptor [1479].
Nomenclature5-ht5a receptor5-ht5b receptor5-HT6 receptor5-HT7 receptor
HGNC, UniProtHTR5A, P47898HTR5BP, –HTR6, P50406HTR7, P34969
Selective agonistsWAY-181187 (pKi 8.7) [1663], E6801 (Partial agonist) (pKi 8.7) [769], WAY-208466 (pKi 8.3) [135], EMD-386088 (pIC50 8.1) [1228]LP-12 (pKi 9.9) [1082], LP-44 (pKi 9.7) [1082], LP-211 (pKi 9.2) [1083] – Rat, AS-19 (pKi 9.2) [947], E55888 (pKi 8.6) [206]
Antagonistslurasidone (pKi 9.3) [829], pimozide (pKi 9.3) [1604] – Rat, vortioxetine (pKi 6.3) [90]
Selective antagonistsSB 699551 (pKi 8.2) [366]SB399885 (pKi 9) [763], SB 271046 (pKi 8.9) [224], cerlapirdine (pKi 8.9) [358], SB357134 (pKi 8.5) [225], Ro 63-0563 (pKi 7.9–8.4) [168, 1754]SB269970 (pKi 8.6–8.9) [1874], SB656104 (pKi 8.7) [531], DR-4004 (pKi 8.7) [615, 938], JNJ-18038683 (pKi 8.2) [177], SB 258719 (Inverse agonist) (pKi 7.5) [1875]
Labelled ligands[125I]LSD (Agonist) (pKd 9.7) [636], [3H]5-CT (Agonist) (pKd 8.6) [636][125I]LSD (Agonist) (pKd 9.3) [1227] – Mouse, [3H]5-CT (Agonist) [1965] – Mouse[11C]GSK215083 (Antagonist) (pKi 9.8) [1462], [125I]SB258585 (Selective Antagonist) (pKd 9) [763], [3H]LSD (Agonist) (pKd 8.7) [167], [3H]Ro 63-0563 (Antagonist) (pKd 8.3) [168], [3H]5-CT (Agonist)[3H]5-CT (Agonist) (pKd 9.4) [1874], [3H]5-HT (Agonist) (pKd 8.1–9) [93, 1793], [3H]SB269970 (Selective Antagonist) (pKd 8.9) [1874], [3H]LSD (Agonist) (pKd 8.5–8.6) [1793]

Comments

Tabulated pKi and KD values refer to binding to human 5-HT receptors unless indicated otherwise. The nomenclature of 5-HT1B/5-HT1D receptors has been revised [707]. Only the non-rodent form of the receptor was previously called 5-HT1D: 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, and ketanserin is a potent α1 adrenoceptor antagonist, in addition to blocking 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 [1404]. The human orthologue of the mouse 5-ht5b receptor is non-functional due to interruption of the gene by stop codons. The 5-ht1e receptor appears not to have been cloned from mouse, or rat, impeding definition of its function. In addition to the receptors listed in the table, an 'orphan' receptor, unofficially termed 5-HT1P, has been described [600].

Further Reading

Bockaert J et al. (2011) 5-HT(4) receptors, a place in the sun: act two. Curr Opin Pharmacol11: 87-93 [PMID:21342787]

Codony X et al. (2011) 5-HT(6) receptor and cognition. Curr Opin Pharmacol11: 94-100 [PMID:21330210]

Hartig PR et al. (1996) Alignment of receptor nomenclature with the human genome: classification of 5-HT1B and 5-HT1D receptor subtypes. Trends Pharmacol. Sci.17: 103-5 [PMID:8936345]

Hayes DJ et al. (2011) 5-HT receptors and reward-related behaviour: a review. Neurosci Biobehav Rev35: 1419-49 [PMID:21402098]

Hoyer D et al. (1994) International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). Pharmacol. Rev.46: 157-203 [PMID:7938165]

Leopoldo M et al. (2011) Serotonin 5-HT7 receptor agents: Structure-activity relationships and potential therapeutic applications in central nervous system disorders. Pharmacol. Ther.129: 120-48 [PMID:20923682]

Meltzer HY et al. (2011) The role of serotonin receptors in the action of atypical antipsychotic drugs. Curr Opin Pharmacol11: 59-67 [PMID:21420906]

Roberts AJ et al. (2012) The 5-HT(7) receptor in learning and memory. Hippocampus22: 762-71 [PMID:21484935]

Sargent BJ et al. (2011) Targeting 5-HT receptors for the treatment of obesity. Curr Opin Pharmacol11: 52-8 [PMID:21330209]

Acetylcholine receptors (muscarinic)

Overview

Muscarinic acetylcholine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Muscarinic Acetylcholine Receptors [275]) are GPCRs of the Class A, rhodopsin-like family where the endogenous agonist is acetylcholine. In addition to the agents listed in the table, AC-42, its structural analogues AC-260584 and 77-LH-28-1, N-desmethylclozapine, TBPB and LuAE51090 have been described as functionally selective agonists of the M1 receptor subtype via binding in a mode distinct from that utilized by non-selective agonists [71, 878, 1040, 1041, 1232, 1635, 1786, 1787, 1825]. There are two pharmacologically characterised allosteric sites on muscarinic receptors, one defined by it binding gallamine, strychnine and brucine, and the other defined by the binding of KT 5720, WIN 62,577, WIN 51,708 and staurosporine[1052, 1053].

NomenclatureM1 receptorM2 receptor
HGNC, UniProtCHRM1, P11229CHRM2, P08172
Agonistscarbachol (pKi 3.2–5.3) [334, 846, 2040], pilocarpine (Partial agonist) (pKi 5.1) [846], bethanechol (pKi 4) [846]bethanechol (pKi 4) [846]
Antagonistsglycopyrrolate (pIC50 9.9) [1801], umeclidinium (pKi 9.8) [1035, 1632], AE9C90CB (pKi 9.7) [1749], propantheline (pKi 9.7) [797], atropine (pKi 8.5–9.6) [334, 552, 759, 797, 1486, 1762], tiotropium (pKi 9.6) [428], 4-DAMP (pKi 9.2) [458], dicyclomine (pKi 9.1) [68], scopolamine (pKi 9) [797], trihexyphenidyl (pKi 8.9) [68], tripitramine (pKi 8.8) [1176], UH-AH 37 (pKi 8.6–8.7) [609, 2012], tolterodine (pKi 8.5–8.7) [609, 1749], oxybutynin (pKi 8.6) [410, 818, 1749], darifenacin (pKi 7.5–8.3) [609, 730, 759, 818, 1749], pirenzepine (pKi 7.8–8.3) [238, 458, 730, 797, 875, 2012], solifenacin (pKi 7.6) [818, 1749], AFDX384 (pKi 7.5) [458], AQ-RA 741 (pKi 7.2–7.5) [458, 609], methoctramine (pKi 6.6–7.3) [458, 493, 730, 1762], himbacine (pKi 6.7–7.1) [458, 875, 1286], muscarinic toxin 3 (pKi 7.1) [875], otenzepad (pKd 6.2) [493]tiotropium (pKi 9.9) [428], umeclidinium (pKi 9.8) [1035, 1632], propantheline (pKi 9.5) [797], glycopyrrolate (Full agonist) (pIC50 9.3) [1801], atropine (pKi 7.8–9.2) [238, 310, 759, 797, 1002, 1373, 1486], AE9C90CB (pKi 8.6) [1749], tolterodine (Inverse agonist) (pKi 8.4–8.6) [609, 1373, 1749], AQ-RA 741 (pKi 8.4) [458, 609], himbacine (pKi 7.9–8.4) [458, 875, 1002, 1286], methoctramine (pKi 7.3–8.4) [238, 458, 493, 730, 1002, 1373], 4-DAMP (pKi 8.3) [1002], AFDX384 (pKi 8.2) [458], biperiden (pKd 8.2) [173], oxybutynin (pKi 7.7–8.1) [818, 1749], darifenacin (Inverse agonist) (pKi 7–7.6) [609, 730, 759, 818, 1373, 1749], UH-AH 37 (pKi 7.3–7.4) [609, 2012], otenzepad (pKi 6.7–7.2) [238, 1002], solifenacin (pKi 6.9–7.1) [818, 1749], pirenzepine (pKi 6–6.7) [238, 458, 730, 797, 875, 1002, 1373, 2012], VU0255035 (pKi 6.2) [1717], muscarinic toxin 3 (pKi<6) [875], guanylpirenzepine (pKi 5.3) [1966] – Rat, muscarinic toxin 7 (pKi<5) [1414]
Selective antagonistsbiperiden (pKd 9.3) [173], VU0255035 (pKi 7.8) [1717], guanylpirenzepine (pKi 7.3–7.6) [23, 1966] – Rattripitramine (pKi 9.6) [1176]
Allosteric modulatorsmuscarinic toxin 7 (Negative) (pKi 11–11.1) [1414], benzoquinazolinone 12 (Positive) (pKB 6.6) [4], KT 5720 (Positive) (pKd 6.4) [1052], brucine (Positive) (pKd 4.5–5.8) [846, 1051], BQCA (Positive) (pKB 4–4.8) [4, 5, 261, 1161], VU0029767 (Positive) [1208], VU0090157 (Positive) [1208]W-84 (Negative) (pKd 6–7.5) [1299, 1908], C7/3-phth (Negative) (pKd 7.1) [335], alcuronium (Negative) (pKd 6.1–6.9) [846, 1908], gallamine (Negative) (pKd 5.9–6.3) [348, 1049], LY2119620 (Positive) (pKd 5.7) [383, 1010], LY2033298 (Positive) (pKd 4.4) [1933]
Labelled ligands[3H]QNB (Antagonist) (pKd 10.6–10.8) [336, 1486], Cy3B-telenzepine (Antagonist) (pKd 10.5) [742], [3H]N-methyl scopolamine (Antagonist) (pKd 9.4–10.3) [280, 334, 336, 759, 846, 847, 875, 932, 1049], [3H](+)telenzepine (Antagonist) (pKi 9.4) [500] – Rat, Alexa-488-telenzepine (Antagonist) (pKd 9.3) [742], [3H]pirenzepine (Antagonist) (pKd 7.9) [1995], BODIPY-pirenzepine (Antagonist) (pKi 7) [820], [11C]butylthio-TZTP (Agonist) [504], [11C]xanomeline (Agonist) [504], [18F](R,R)-quinuclidinyl-4-fluoromethyl-benzilate (Antagonist) [935] – Rat[3H]QNB (Antagonist) (pKd 10.1–10.6) [1486], Cy3B-telenzepine (Antagonist) (pKi 10.4) [1380], [3H]tiotropium (Antagonist) (pKd 10.3) [1632], [3H]N-methyl scopolamine (Antagonist) (pKd 9.3–9.9) [280, 310, 759, 846, 847, 875, 932, 1049, 1985], Alexa-488-telenzepine (Antagonist) (pKi 8.8) [1380], [3H]acetylcholine (Agonist) (pKd 8.8) [1050], [3H]oxotremorine-M (Agonist) (pKd 8.7) [137], [3H]dimethyl-W84 (Allosteric modulator, Positive) (pKd 8.5) [1908], [18F]FP-TZTP (Agonist) [845] – Mouse
NomenclatureM3 receptorM4 receptorM5 receptor
HGNC, UniProtCHRM3, P20309CHRM4, P08173CHRM5, P08912
Agonistspilocarpine (Partial agonist) (pKi 5.1) [846], carbachol (pKi 4–4.4) [310, 846, 2040], bethanechol (pKi 4.2) [846]pilocarpine (Partial agonist) (pKi 5.2) [846], carbachol (pKi 4.3–4.9) [846, 2040], bethanechol (pKi 4) [846]pilocarpine (Partial agonist) (pKi 5) [639], carbachol (pKi 4.9) [2040]
Antagoniststiotropium (pKi 9.5–11.1) [428, 442], umeclidinium (pKi 10.2) [1035, 1632], propantheline (pKi 10) [797], AE9C90CB (pKi 9.9) [1749], atropine (pKi 8.9–9.8) [238, 442, 759, 797, 1486, 1762], ipratropium (pKi 9.3–9.8) [442, 759], aclidinium (pIC50 9.8) [1530], clidinium (pKi 9.6) [442], glycopyrrolate (pIC50 9.6) [1801], 4-DAMP (pKi 9.3) [458], darifenacin (pKi 8.6–9.1) [609, 730, 759, 818, 1749], dicyclomine (pKi 9) [68], oxybutynin (pKi 8.8–8.9) [410, 818, 1749], tolterodine (pKi 8.4–8.5) [609, 1749], biperiden (pKd 8.4) [173], UH-AH 37 (pKi 8.1–8.2) [609, 2012], solifenacin (pKi 7.7–8) [818, 1749], tropicamide (pKi 7.5) [68], AQ-RA 741 (pKi 7.2–7.3) [458, 609], AFDX384 (pKi 7.2) [458], himbacine (pKi 6.9–7.2) [458, 875, 1286], methoctramine (pKi 6.1–6.9) [238, 458, 493, 730, 1762], tripitramine (pKi 6.8) [1288], pirenzepine (pKi 6.5–6.8) [238, 458, 730, 797, 875, 2012], guanylpirenzepine (pKi 6.2) [1966] – Rat, VU0255035 (pKi 6.1) [1717], otenzepad (pKi 6.1) [238], muscarinic toxin 3 (pKi<6) [875], muscarinic toxin 7 (pKi<5) [1414]umeclidinium (pKi 10.3) [1632], glycopyrrolate (pIC50 9.8) [1801], AE9C90CB (pKi 9.5) [1749], 4-DAMP (pKi 8.9) [458], oxybutynin (pKi 8.7) [1749], biperiden (pKd 8.6) [173], UH-AH 37 (pKi 8.3–8.4) [609, 2012], tolterodine (pKi 8.3–8.4) [609, 1749], AQ-RA 741 (pKi 7.8–8.2) [458, 609], himbacine (pKi 7.9–8.2) [458, 875, 1286], darifenacin (pKi 7.3–8.1) [609, 730, 759, 1749], AFDX384 (pKi 8) [458], tripitramine (pKi 7.9) [1288], pirenzepine (pKi 7–7.6) [458, 730, 797, 875, 2012], methoctramine (pKi 6.6–7.5) [238, 458, 493, 730], otenzepad (pKd 7) [493], solifenacin (pKi 6.8) [1749], guanylpirenzepine (pKi 6.2) [1966] – Rat, VU0255035 (pKi 5.9) [1717], muscarinic toxin 7 (pKi<5) [1414]umeclidinium (pKi 9.9) [1632], glycopyrrolate (pIC50 9.7) [1801], AE9C90CB (pKi 9.5) [1749], 4-DAMP (pKi 9) [458], tolterodine (pKi 8.5–8.8) [609, 1749], darifenacin (pKi 7.9–8.6) [609, 730, 759, 1749], UH-AH 37 (pKi 8.3) [609, 2012], biperiden (pKd 8.2) [173], oxybutynin (pKi 7.9) [1749], AQ-RA 741 (pKi 6.1–7.8) [458, 609], tripitramine (pKi 7.5) [1176], methoctramine (pKi 6.3–7.2) [238, 458, 493, 730], solifenacin (pKi 7.2) [1749], pirenzepine (pKi 6.8–7.1) [730, 875, 2012], guanylpirenzepine (pKd 6.8) [514] – Unknown, himbacine (pKi 5.4–6.5) [458, 875, 1286], AFDX384 (pKi 6.3) [458], muscarinic toxin 3 (pKi<6) [875], otenzepad (pKi 5.6) [238], muscarinic toxin 7 (pKi<5) [1414]
Selective antagonistsML381 (pKi 6.3) [593]
Allosteric modulatorsWIN 62,577 (Positive) (pKd 5.1) [1053], N-chloromethyl-brucine (Positive) (pKd 3.3) [1051]muscarinic toxin 3 (Negative) (pKi 8.7) [875, 1444], LY2119620 (Positive) (pKd 5.7) [383], thiochrome (Positive) (pKd 4) [1050], LY2033298 (Positive) [286], VU0152099 (Positive) [201], VU0152100 (Positive) [201]ML380 (Positive) (pEC50 6.7) [595]
Selective allosteric modulatorsML375 (Negative) (pIC50 6.5) [594]
Labelled ligands[3H]tiotropium (Antagonist) (pKd 10.7) [1632], [3H]QNB (Antagonist) (pKd 10.4) [1486], [3H]N-methyl scopolamine (Antagonist) (pKd 9.7–10.2) [280, 310, 759, 797, 846, 875, 932, 1049], [3H]darifenacin (Antagonist) (pKd 9.5) [1762][3H]QNB (Antagonist) (pKd 9.7–10.5) [336, 1486], [3H]N-methyl scopolamine (Antagonist) (pKd 9.9–10.2) [280, 310, 336, 759, 846, 875, 932, 1049, 1444, 1985], [3H]acetylcholine (Agonist) (pKd 8.2) [1050][3H]QNB (Antagonist) (pKd 10.2–10.7), [3H]N-methyl scopolamine (Antagonist) (pKd 9.3–9.7) [280, 310, 759, 875, 932, 1985]

Comments

LY2033298 and BQCA have also been shown to directly activate the M4 and M1 receptors, respectively, via an allosteric site [1059, 1060, 1366, 1367]. The allosteric site for gallamine and strychnine on M2 receptors can be labelled by [3H]dimethyl-W84[1908]. McN-A-343 is a functionally selective partial agonist that appears to interact in a bitopic mode with both the orthosteric and an allosteric site on the M2 muscarinic receptor [1934]. THRX160209, hybrid 1 and hybrid 2, are multivalent (bitopic) ligands that also achieve selectivity for M2 receptors by binding both to the orthosteric and a nearby allosteric site [52, 1796].

Although numerous ligands for muscarinic acetylcholine receptors have been described, relatively few selective antagonists have been described, so it is common to assess the rank order of affinity of a number of antagonists of limited selectivity (e.g.4-DAMP, darifenacin, pirenzepine) in order to identify the involvement of particular subtypes. It should be noted that the measured affinities of antagonists (and agonists) in radioligand binding studies are sensitive to ionic strength and can increase over 10-fold at low ionic strength compared to its value at physiological ionic strengths [151].

Further Reading

Caulfield MP et al. (1998) International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors. Pharmacol. Rev.50: 279-290 [PMID:9647869]

Eglen RM. (2012) Overview of muscarinic receptor subtypes. Handb Exp Pharmacol 3-28 [PMID:22222692]

Gregory KJ et al. (2007) Allosteric modulation of muscarinic acetylcholine receptors. Curr Neuropharmacol5: 157-67 [PMID:19305798]

Kruse AC et al. (2014) Muscarinic acetylcholine receptors: novel opportunities for drug development. Nat Rev Drug Discov13: 549-60 [PMID:24903776]

Leach K et al. (2012) Structure-function studies of muscarinic acetylcholine receptors. Handb Exp Pharmacol 29-48 [PMID:22222693]

Valant C et al. (2012) The best of both worlds? Bitopic orthosteric/allosteric ligands of g protein-coupled receptors. Annu. Rev. Pharmacol. Toxicol.52: 153-78 [PMID:21910627]

Adenosine receptors

Overview

Adenosine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Adenosine Receptors [541]) are activated by the endogenous ligand adenosine(potentially inosine also at A3 receptors). Crystal structures for the antagonist-bound and agonist-bound A2A adenosine receptors have been described [835, 2065].

NomenclatureA1 receptorA2A receptorA2B receptorA3 receptor
HGNC, UniProtADORA1, P30542ADORA2A, P29274ADORA2B, P29275ADORA3, P0DMS8
Agonistscyclopentyladenosine (pKi 6.5–9.4) [388, 570, 736, 839, 870, 1592, 2141]
(Sub)family-selective agonistsNECA (pKi 5.3–8.2) [570, 870, 1592, 1903, 2077]NECA (pKi 6.9–8.7) [189, 427, 570, 943, 1021, 2077]NECA (pKi 5.7–6.9) [146, 189, 862, 1113, 1798, 1945, 2077]NECA (pKi 7.5–8.4) [189, 570, 840, 1634, 1946, 2077]
Selective agonists5-Cl-5-deoxy-(±)-ENBA (pKi 9.3) [536], GR79236 (pKi 8.5) [839] – Rat, CCPA (pKi 7.7–8.1) [839, 1419]apadenoson (pKi 9.3) [1481], UK-432,097 (pKi 8.3) [2065], CGS 21680 (pKi 6.7–8.1) [189, 427, 570, 839, 943, 968, 1021, 1419], regadenoson (pKi 6.5) [839]BAY 60-6583 (pKi 8–8.5) [460]IB-MECA (pKi 8.7–9.2) [511, 561, 968, 1946], Cl-IB-MECA (pKi 8–8.9) [202, 840, 941], MRS5698 (pKi 8.5) [1898]
Antagonistscaffeine (pKi 4.3–5) [6, 409, 838]SCH 58261 (pKi 8.3–9.2) [427, 1021, 1445], theophylline (pKi 5.2–5.8) [427, 838, 968, 1945], caffeine (pKi 4.6–5.6) [6, 838, 1021]theophylline (pKi 4.1–5) [141, 511, 944, 1945], caffeine (pKi 4.5–5) [141, 188, 944]caffeine (pKi 4.9) [838]
(Sub)family-selective antagonistsCGS 15943 (pKi 8.5) [1445], xanthine amine congener (pKd 7.5) [536]CGS 15943 (pKi 7.7–9.4) [427, 943, 968, 1445], xanthine amine congener (pKi 8.4–9) [427, 968]xanthine amine congener (pKi 6.9–8.8) [146, 862, 863, 968, 1113, 1798], CGS 15943 (pKi 6–8.1) [65, 862, 863, 968, 1445, 1798]CGS 15943 (pKi 7–7.9) [949, 968, 1445, 1946], xanthine amine congener (pKi 7–7.4) [968, 1634, 1946]
Selective antagonistsPSB36 (pKi 9.9) [6] – Rat, DPCPX (pKi 7.4–9.2) [826, 1419, 1592, 2015, 2141], derenofylline (pKi 9) [897], WRC-0571 (pKi 8.8) [1210]SCH442416 (pKi 8.4–10.3) [1728, 1891], ZM-241385 (pKi 8.8–9.1) [1445]PSB-0788 (pKi 9.4) [188], PSB603 (pKi 9.3) [188], MRS1754 (pKi 8.8) [862, 948], PSB1115 (pKi 7.3) [723]MRS1220 (pKi 8.2–9.2) [840, 949, 1818, 2090], VUF5574 (pKi 8.4) [2143], MRS1523 (pKi 7.7) [1092], MRS1191 (pKi 7.5) [840, 866, 1097]
Labelled ligands[3H]CCPA (Agonist) (pKd 9.2) [968, 1592], [3H]DPCPX (Antagonist) (pKd 8.4–9.2) [388, 511, 968, 1445, 1592, 1903][3H]ZM 241385 (Antagonist) (pKd 8.7–9.1) [36, 569], [3H]CGS 21680 (Agonist) (pKd 7.7–7.8) [852, 1976][3H]MRS1754 (Antagonist) (pKd 8.8) [862][125I]AB-MECA (Agonist) (pKd 9–9.1) [1445, 1946]

Comments

Adenosine inhibits many intracellular ATP-utilising enzymes, including adenylyl cyclase (P-site). A pseudogene exists for the A2B adenosine receptor (ADORA2BP1) with 79% identity to the A2B adenosine receptor cDNA coding sequence, but which is unable to encode a functional receptor [841]. DPCPX also exhibits antagonism at A2B receptors (pKi ca. 7,[34, 968]). 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]ZM 241385 can also be used to label A2B receptors (KDca. 30 and 60 nM respectively). [125I]AB-MECA also binds to A1 receptors [968]. [3H]CGS 21680 is relatively selective for A2A receptors, but may also bind to other sites in cerebral cortex [384, 871]. [3H]NECA binds to other non-receptor elements, which also recognise adenosine [1143]. 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 [212].

Further Reading

Fredholm BB et al. (2011) International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors–an update. Pharmacol. Rev.63: 1-34 [PMID:21303899]

Göblyös A et al. (2011) Allosteric modulation of adenosine receptors. Biochim. Biophys. Acta1808: 1309-18 [PMID:20599682]

Headrick JP et al. (2011) Adenosine and its receptors in the heart: regulation, retaliation and adaptation. Biochim. Biophys. Acta1808: 1413-28 [PMID:21094127]

Lasley RD. (2011) Adenosine receptors and membrane microdomains. Biochim. Biophys. Acta1808: 1284-9 [PMID:20888790]

Mundell S et al. (2011) Adenosine receptor desensitization and trafficking. Biochim. Biophys. Acta1808: 1319-28 [PMID:20550943]

Ponnoth DS et al. (2011) Adenosine receptors and vascular inflammation. Biochim. Biophys. Acta1808: 1429-34 [PMID:20832387]

Wei CJ et al. (2011) Normal and abnormal functions of adenosine receptors in the central nervous system revealed by genetic knockout studies. Biochim. Biophys. Acta1808: 1358-79 [PMID:21185258]

Adhesion Class GPCRs

Overview

Adhesion GPCRs are structurally identified on the basis of a large extracellular region, similar to the Class B GPCR, but which is linked to the 7TM region by a "stalk" motif containing a GPCR proteolytic site. The N-terminus often shares structural homology with proteins such as lectins and immunoglobulins, leading to the term adhesion GPCR [543, 2097]. The nomenclature of these receptors was revised in 2015 as recommended by NC-IUPHAR and the Adhesion GPCR Consortium [683].

NomenclatureADGRA1ADGRA2ADGRA3ADGRB1ADGRB2
HGNC, UniProtADGRA1, Q86SQ6ADGRA2, Q96PE1ADGRA3, Q8IWK6ADGRB1, O14514ADGRB2, O60241
Endogenous agonistsphosphatidylserine [1461]
CommentsADGRB1 is reported to respond to phosphatidylserine [1461].
NomenclatureADGRF5ADGRG1ADGRG2ADGRG3ADGRG4
HGNC, UniProtADGRF5, Q8IZF2ADGRG1, Q9Y653ADGRG2, Q8IZP9ADGRG3, Q86Y34ADGRG4, Q8IZF6
CommentsReported to bind tissue transglutaminase 2 [2066] and collagen, which activates the G12/13 pathway [1155].
NomenclatureADGRL2ADGRL3ADGRL4ADGRV1
HGNC, UniProtADGRL2, O95490ADGRL3, Q9HAR2ADGRL4, Q9HBW9ADGRV1, Q8WXG9
CommentsLoss-of-function mutations are associated with Usher syndrome, a sensory deficit disorder [843].

Adrenoceptors

Overview

Adrenoceptors, α1

α1-Adrenoceptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [248], see also [752]) are 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 antagonists 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. The α1A-adrenoceptor antagonist S(+)-niguldipine also has high affinity for L-type Ca2+ channels. The conotoxin rho-TIA acts as a negative allosteric modulator at the α1B-adrenoceptor [1716], while the snake toxin ρ-Da1a acts as a selective non-competitive antagonist at the α1A-adrenoceptor [1236, 1548]. Fluorescent derivatives of prazosin (Bodipy PL-prazosin-QAPB) are increasingly used to examine cellular localisation of α1-adrenoceptors. The vasoconstrictor effects of selective α1-adrenoceptor agonists have led to their use as nasal decongestants; antagonists are used to treat hypertension (doxazosin, prazosin) and benign prostatic hyperplasia (alfuzosin, tamsulosin). The combined α1- and β2-adrenoceptor antagonist carvedilol is widely used to treat congestive heart failure, although the contribution of α1-adrenoceptor blockade to the therapeutic effect is unclear. Several anti-depressants and anti-psychotic drugs possess α1-adrenoceptor blocking properties that are believed to contribute to side effects such as orthostatic hypotension and extrapyramidal effects.

Nomenclatureα1A-adrenoceptorα1B-adrenoceptorα1D-adrenoceptor
HGNC, UniProtADRA1A, P35348ADRA1B, P35368ADRA1D, P25100
Endogenous agonists(-)-adrenaline (pKi 7.2) [1722]
Agonistsoxymetazoline (pKi 8–8.2) [780, 1420, 1722, 1862], phenylephrine (pKi 5.2–5.4) [1862], methoxamine (pKi 5–5.2) [1722, 1862]phenylephrine (pIC50 6.3–7.5) [532, 1289]
Selective agonistsA61603 (pIC50 7.8–8.4) [532, 969], dabuzalgron (pKi 7.4) [162]
Antagonistsprazosin (Inverse agonist) (pKi 9–9.9) [289, 389, 532, 1722, 2029], doxazosin (pKi 9.3) [689], terazosin (pKi 8.7) [1263], phentolamine (pKi 8.6) [1722], alfuzosin (pKi 8.1) [750]prazosin (Inverse agonist) (pKi 9.6–9.9) [532, 1722, 2029], tamsulosin (Inverse agonist) (pKi 9.5–9.7) [532, 1722, 2029], doxazosin (pKi 9.1) [689], alfuzosin (pKi 8.6) [751], terazosin (pKi 8.6) [1263], phentolamine (pKi 7.5) [1722]prazosin (Inverse agonist) (pKi 9.5–10.2) [532, 1722, 2029], tamsulosin (pKi 9.8–10.2) [532, 1722, 2029], doxazosin (pKi 9.1) [689], terazosin (pKi 9.1) [1263], alfuzosin (pKi 8.4) [750], dapiprazole (pKi 8.4) [68], phentolamine (Inverse agonist) (pKi 8.2) [1722], RS-100329 (pKi 7.9) [2029], labetalol (pKi 6.6) [68]
Selective antagoniststamsulosin (pKi 10–10.7) [289, 389, 532, 1722, 2029], silodosin (pKi 10.4) [1722], S(+)-niguldipine (pKi 9.1–10) [532, 1722], RS-100329 (pKi 9.6) [2029], SNAP5089 (pKi 8.8–9.4) [750, 1081, 2014], ρ-Da1a (pKi 9.2–9.3) [1236, 1548], RS-17053 (pKi 9.2–9.3) [289, 389, 529, 532]Rec 15/2615 (pKi 9.5) [1867], L-765314 (pKi 7.7) [1470], AH 11110 (pKi 7.5) [1652]BMY-7378 (pKi 8.7–9.1) [268, 2102]

Adrenoceptors, α2

α2-Adrenoceptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Adrenoceptors; [248]) are activated by endogenous agonists with a relative potency of (-)-adrenaline>(-)-noradrenaline. Brimonidine and talipexole are agonists selective for α2-adrenoceptors relative to α1-adrenoceptors, rauwolscine and yohimbine are antagonists selective for α2-adrenoceptors relative to α1-adrenoceptors. [3H]rauwolscine(1 nM), [3H]brimonidine(5 nM) and [3H]RX821002(0.5 nM 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 higher affinity for the human α2A-adrenoceptor compared to the rat, mouse and bovine 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. Presynaptic α2-adrenoceptors are widespread in the nervous system and regulate many functions, hence the multiplicity of actions. The effects of classical (not subtype selective) α2-adrenoceptor agonists such as clonidine, guanabenz and brimonidine on central baroreflex control (hypotension and bradycardia), as well as their ability to induce hypnotic effects and analgesia, and their ability to modulate seizure activity and platelet aggregation are mediated by α2A-adrenoceptors. Clonidine has been used as an anti-hypertensive and also to counteract opioid withdrawal. Actions on imidazoline recognition sites may contribute to the pharmacological effects of clonidine. α2-Adrenoceptor agonists such as dexmedetomidine have been widely used as sedatives and analgesics in veterinary medicine (also xylazine) and are now used frequently in humans. Dexmedetomidine also has analgesic, sympatholytic and anxiolytic properties but is notable for the production of sedation without respiratory depression. α2-Adrenoceptor antagonists are relatively little used therapeutically although yohimbine has been used to treat erectile dysfunction and several anti-depressants (e.g. Mirtazapine) that block α2-adrenoceptors may work through this mechanism. The roles of α2B and α2C-adrenoceptors are less clear but the α2B subtype appears to be involved in neurotransmission in the spinal cord and α2C in regulating catecholamine release from adrenal chromaffin cells.

Nomenclatureα2A-adrenoceptorα2B-adrenoceptorα2C-adrenoceptor
HGNC, UniProtADRA2A, P08913ADRA2B, P18089ADRA2C, P18825
Endogenous agonists(-)-adrenaline (pKi 5.6–8.3) [854, 1503](-)-noradrenaline (Partial agonist) (pKi 5.6–9.1) [854, 1484, 1503](-)-noradrenaline (pKi 5.9–8.7) [854, 1484, 1503]
Agonistsdexmedetomidine (Partial agonist) (pKi 7.6–9.6) [854, 1163, 1484, 1503], clonidine (Partial agonist) (pKi 7.2–9.2) [854, 1484, 1503], brimonidine (pKi 6.7–8.7) [854, 1163, 1484, 1503], apraclonidine (pKi 8.5) [1343], guanabenz (pIC50 7.4) [68], guanfacine (Partial agonist) (pKi 7.1–7.3) [854, 1165]dexmedetomidine (pKi 7.5–9.7) [854, 1163, 1484, 1503], clonidine (Partial agonist) (pKi 6.7–9.5) [854, 1484, 1503], brimonidine (Partial agonist) (pKi 6–8.3) [854, 1484, 1503], guanabenz (pIC50 6.8) [68], guanfacine (pKi 5.8–6.5) [854]dexmedetomidine (pKi 7–9.3) [854, 1484, 1503], brimonidine (Partial agonist) (pKi 5.7–7.6) [854, 1163, 1484, 1503], apraclonidine (pKi 7.5) [1343], guanfacine (Partial agonist) (pKi 5.4–6.2) [854], guanabenz (pIC50 6) [68]
Selective agonistsoxymetazoline (Partial agonist) (pKi 8–8.6) [854, 1163, 1922]
Antagonistsyohimbine (pKi 8.5–9.5) [247, 416, 1922], WB 4101 (pKi 8.4–9.4) [247, 416, 1922], spiroxatrine (pKi 9) [1922], mirtazapine (pKi 7.7) [513], tolazoline (pKi 5.4) [854]yohimbine (pKi 8.4–9.2) [247, 416, 1922]yohimbine (pKi 7.9–8.9) [247, 416, 1922], phenoxybenzamine (pKi 8.5) [2002], tolazoline (pKi 5.5) [854]
Selective antagonistsBRL 44408 (pKi 8.2–8.8) [1922, 2104]imiloxan (pKi 7.3) [1269] – RatJP1302 (pKB 7.8) [1631]
Labelled ligands[3H]MK-912 (Antagonist) (pKd 10.1) [1922]

Adrenoceptors, β

β-Adrenoceptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Adrenoceptors, [248]) are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. Isoprenaline is a synthetic agonist selective for β-adrenoceptors relative to α1- and α2-adrenoceptors, while for β1 and β2 adrenoceptors, propranolol(pKi8.2-9.2) and cyanopindolol(pKi 10.0-11.0) are relatively selective antagonists. (-)-noradrenaline, xamoterol and (-)-Ro 363 are agonists that show selectivity for β1- relative to β2-adrenoceptors. Pharmacological differences exist between human and mouse β3-adrenoceptors, and the 'rodent selective' agonists BRL 37344 and CL316243 have low efficacy at the human β3-adrenoceptor whereas CGP 12177 and L 755507 activate human β3-adrenoceptors [1649]. β3-Adrenoceptors are relatively resistant to blockade by propranolol(pKi5.8-7.0), but can be blocked by high concentrations of bupranolol(pKi8.65 [1650]). SR59230A has reasonably high affinity at β3-adrenoceptors [1197], but does not discriminate well between the three β-adrenoceptor subtypes [262] and has been reported to have lower affinity for the β3-adrenoceptor in some circumstances [913]. L-748337 is the most selective antagonist for β3 adrenoceptors. [125I]-cyanopindolol, [125I]-hydroxybenzylpindolol and [3H]-alprenolol are high affinity radioligands widely used to label β1- and β2-adrenoceptors and β3-adrenoceptors can be labelled with higher concentrations (nM) of [125I]-cyanopindolol in the presence of appropriate concentrations of β1- and β2-adrenoceptor antagonists. [3H]L-748337 is a β3-selective radioligand. Fluorescent ligands such as BODIPY-TMR-CGP12177 are also increasingly being used to track β-adrenoceptors at the cellular level [86]. Somewhat selective β1-adrenoceptor selective agonists (denopamine, dobutamine) are used short-term to treat cardiogenic shock but, in the longer term, reduce survival. β1-Adrenoceptor-preferring antagonists are used to treat hypertension (atenolol, betaxolol, bisoprolol, metoprolol and nebivolol), cardiac arrhythmias (atenolol, bisoprolol, esmolol) and cardiac failure (metoprolol, nebivolol). Cardiac failure is also succesfully treated with carvedilol which blocks both β1- and β2-adrenoceptors, as well as α1-adrenoceptors. β2-Adrenoceptor-selective agonists are powerful bronchodilators widely used to treat respiratory disorders. There are both short (salbutamol, terbutaline) and long acting drugs (formoterol, salmeterol). Although many first generation β-adrenoceptor antagonists (propranolol) block both β1- and β2-adrenoceptors there are no β2-adrenoceptor-selective antagonists used therapeutically. The β3-adrenoceptor agonist mirabegron is used to control overactive bladder syndrome.

Nomenclatureβ1-adrenoceptorβ2-adrenoceptorβ3-adrenoceptor
HGNC, UniProtADRB1, P08588ADRB2, P07550ADRB3, P13945
Rank order of potency(-)-noradrenaline>(-)-adrenaline(-)-adrenaline>(-)-noradrenaline(-)-noradrenaline = (-)-adrenaline
Endogenous agonistsnoradrenaline (pKi 6) [549]
Agonistspindolol (Partial agonist) (pKi 9.3) [1011], isoprenaline (pKi 6.6–7) [549, 1651], dobutamine (Partial agonist) (pKi 5.5) [831]pindolol (Partial agonist) (pKi 9.4) [1011], arformoterol (pKi 8.6) [37], isoprenaline (pKi 6.4) [1651], dobutamine (Partial agonist) (pKi 6.2) [1100], ephedrine (Partial agonist) (pKi 5.6) [851]carazolol (pKi 8.7) [1256]
Selective agonists(-)-Ro 363 (pKi 8) [1301], xamoterol (Partial agonist) (pKi 7) [831], denopamine (Partial agonist) (pKi 5.8) [831, 1830]formoterol (pEC50 10.1) [81], salmeterol (pEC50 9.9) [81], zinterol (pEC50 9.5) [81], vilanterol (pEC50 9.4) [1534], procaterol (pEC50 8.4) [81], indacaterol (pKi 7.8) [107], fenoterol (pKi 6.9) [55], salbutamol (Partial agonist) (pKi 5.8–6.1) [83, 831], terbutaline (Partial agonist) (pKi 5.6) [83], orciprenaline (pKd 5.3) [1784]L 755507 (pEC50 10.1) [81], L742791 (pEC50 8.8) [2000], mirabegron (pEC50 7.7) [1849], CGP 12177 (Partial agonist) (pKi 6.1–7.3) [159, 1144, 1256, 1301], SB251023 (pEC50 7.1) [810] – Mouse, BRL 37344 (pKi 6.4–7) [159, 431, 768, 1256], CL316243 (pKi 5.2) [2080]
Antagonistscarvedilol (pKi 9.5) [262], bupranolol (pKi 7.3–9) [262, 1144], levobunolol (pKi 8.4) [68], labetalol (pKi 8.2) [68], metoprolol (pKi 7–7.6) [83, 262, 768, 1144], esmolol (pKi 6.9) [68], nadolol (pKi 6.9) [262], practolol (pKi 6.1–6.8) [83, 1144], propafenone (pKi 6.7) [68], sotalol (pKi 6.1) [68]carvedilol (pKi 9.4–9.9) [83, 262], timolol (pKi 9.7) [83], propranolol (pKi 9.1–9.5) [83, 86, 831, 1144], levobunolol (pKi 9.3) [68], bupranolol (pKi 8.3–9.1) [262, 1144], alprenolol (pKi 9) [83], nadolol (pKi 7–8.6) [83, 262], labetalol (pKi 8) [68], propafenone (pKi 7.4) [68], sotalol (pKi 6.5) [68]carvedilol (pKi 9.4) [262], bupranolol (pKi 6.8–7.3) [159, 262, 1144, 1256], propranolol (pKi 6.3–7.2) [1144, 1517], levobunolol (pKi 6.8) [1517]
Selective antagonistsCGP 20712A (pKi 8.5–9.2) [83, 262, 1144], levobetaxolol (pKi 9.1) [1715], betaxolol (pKi 8.8) [1144], nebivolol (pIC50 8.1–8.7) [1476] – Rabbit, atenolol (pKi 6.7–7.6) [83, 886, 1144], acebutolol (pKi 6.4) [68]ICI 118551 (Inverse agonist) (pKi 9.2–9.5) [83, 86, 1144]L-748337 (pKi 8.4) [262], SR59230A (pKi 6.9–8.4) [262, 405, 768], L748328 (pKi 8.4) [262]
Labelled ligands[125I]ICYP (Selective Antagonist) (pKd 10.4–11.3) [831, 1144, 1651][125I]ICYP (Antagonist) (pKd 11.1) [1144, 1651][125I]ICYP (Agonist, Partial agonist) (pKd 9.2–9.8) [1144, 1301, 1517, 1651, 1806]
CommentsThe agonists indicated have less than two orders of magnitude selectivity [81].Agonist SB251023 has a pEC50 of 6.9 for the splice variant of the mouse β3 receptor, β3b [810].

Comments

Adrenoceptors, α1

The clone originally called the α1C-adrenoceptor corresponds to the pharmacologically defined α1A-adrenoceptor [752]. Some tissues possess α1A-adrenoceptors (termed α1L-adrenoceptors [532, 1329]) that display relatively low affinity in functional and binding assays for prazosin(pKi< 9) indicative of different receptor states or locations. α1A-adrenoceptor C-terminal splice variants form homo- and heterodimers, but fail to generate a functional α1L-adrenoceptor [1557]. α1D-Adrenoceptors form heterodimers with α1B- or β2-adrenoceptors that show increased cell-surface expression [1917]. Recombinant α1D-adrenoceptors have been shown in some heterologous systems to be mainly located intracellularly but cell-surface localization is attained by truncation of the N-terminus, or by co-expression of α1B- or β2-adrenoceptors to form heterodimers [670, 1917]. In smooth muscle of native blood vessels all three α1-adrenoceptor subtypes are located on the surface and intracellularly [1260, 1261].

Signalling is predominantly via Gq/11 but α1-adrenoceptors also couple to Gi/o, Gs and G12/13. Several ligands activating α1A-adrenoceptors display ligand directed signalling bias relative to noradrenaline. For example, oxymetazoline is a full agonist for extracellular acidification rate (ECAR) and a partial agonist for Ca2+ release but does not stimulate cAMP production. Phenylephrine is biased toward ECAR versus Ca2+ release or cAMP accumulation but not between Ca2+ release and cAMP accumulation [495]. There are also differences between subtypes in coupling efficiency to different pathways- e.g. in some systems coupling efficiency to Ca2+ signalling is α1A>α1B>α1D, but for MAP kinase signalling is α1D>α1A>α1B. In vascular smooth muscle, the potency of agonists is related to the predominant subtype, α1D- conveying greater agonist sensitivity than α1A-adrenoceptors [526].

Adrenoceptors, α2

ARC-239(pKi 8.0) and prazosin(pKi 7.5) show selectivity for α2B- and α2C-adrenoceptors over α2A-adrenoceptors.Oxymetazoline is a reduced efficacy agonist and is one of many α2-adrenoceptor agonists that are imidazolines or closely related compounds. Other binding sites for imidazolines, distinct from α2-adrenoceptors, and structurally distinct from the 7TM adrenoceptors, have been identified and classified as I1, I2 and I3sites [390]; catecholamines have a low affinity, while rilmenidine and moxonidine are selective ligands for these sites, evoking hypotensive effects in vivo. I1-imidazoline receptors are involved in central inhibition of sympathetic tone, I2-imidazoline receptors are an allosteric binding site on monoamine oxidase B, and I3-imidazoline receptors regulate insulin secretion from pancreatic β-cells. α2A-adrenoceptor stimulation reduces insulin secretion from β-islets [2083], with a polymorphism in the 5'-UTR of the ADRA2A gene being associated with increased receptor expression in β-islets and heightened susceptibility to diabetes [1599].

α2A- and α2C-adrenoceptors form homodimers [1758]. Heterodimers between α2A- and either the α2c-adrenoceptor or μ opioid peptide receptor exhibit altered signalling and trafficking properties compared to the individual receptors [1758, 1858, 1956]. Signalling by α2-adrenoceptors is primarily via Gi/o, however the α2A-adrenoceptor also couples to Gs[459]. Imidazoline compounds display bias relative to each other at the α2A-adrenoceptor when assayed by [35S] GTPγS binding compared to inhibition of cAMP accumulation [1477]. The noradrenaline reuptake inhibitor desipramine acts directly on the α2A-adrenoceptor, promoting internalisation via recruitment of arrestin without activating G proteins [371].

Adrenoceptors, β

Radioligand binding with [125I]ICYP can be used to define β1- or β2-adrenoceptors when conducted in the presence of a 'saturating' concentration of either a 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 CGP 12177 to β2-adrenoceptors in living cells has been described [84]. [125I]ICYP at higher (nM) concentrations can be used to label β3-adrenoceptors in systems where there are few if any other β-adrenoceptor subtypes. Pharmacological differences exist between human and mouse β3-adrenoceptors, and the 'rodent selective' agonists BRL 37344 and CL316243 are partial agonists at the human β3-adrenoceptor whereas CGP 12177 and L 755507 activate human β3-adrenoceptors with greater potency [1650]. The β3-adrenoceptor has an intron in the coding region, but splice variants have only been described for the mouse [496], where the isoforms display different signalling characteristics [810]. There are 3 β-adrenoceptors in turkey (termed the tβ, tβ3c and tβ4c) that have a pharmacology that differs from the human β-adrenoceptors [82]. Numerous polymorphisms have been described for the three β-adrenoceptors; some are associated with alterations in agonist-evoked signalling and trafficking, altered susceptibility to disease and/or altered responses to pharmacotherapy [1103].

All β-adrenoceptors couple to Gs(activating adenylyl cyclase and elevating cAMP levels), but it is also clear that they activate other G proteins such as Gi and many other G protein-independent signalling pathways, including arrestin-mediated signalling, which may in turn lead to activation of MAP kinases. Many antagonists at β1- and β2-adrenoceptors are agonists at β3-adrenoceptors (CL316243, CGP 12177 and carazolol). Many ‘antagonists’ that block agonist-stimulated cAMP accumulation, for example carvedilol and bucindolol, are able to activate MAP kinase pathways [85, 497, 559, 560, 1649, 1650] and thus display 'protean agonism'. Bupranolol appears to act as a neutral antagonist in most systems so far examined. Agonists also display biased signalling at the β2-adrenoceptor via Gs or arrestins [443].

The X-ray crystal structures have been described of the agonist bound [1988] and antagonist bound forms of the β1- [1989], agonist-bound [313] and antagonist-bound forms of the β2-adrenoceptor [1561, 1598], as well as a fully active agonist-bound, Gs protein-coupled β2-adrenoceptor [1562]. Carvedilol and bucindolol bind to an extended site of the β1-adrenoceptor involving contacts in TM2, 3, and 7 and extracellular loop 2 that may facilitate coupling to arrestins [1989]. Compounds displaying arrestin-biased signalling at the β2-adrenoceptor also have a greater effect on the conformation of TM7, whereas full agonists for Gs coupling promote movement of TM5 and TM6 [1127]. Recent studies using NMR spectroscopy have demonstrated significant conformational flexibility in the β2-adrenoceptor which is stabilized by both agonist and G proteins highlighting the dynamic nature of interactions with both ligand and downstream signalling partners [946, 1199, 1413]. Such flexibility will likely have consequences for our understanding of biased agonism, and for the future therapeutic exploitation of this phenomenon.

Further Reading

Baker JG et al. (2011) Evolution of β-blockers: from anti-anginal drugs to ligand-directed signalling. Trends Pharmacol. Sci.32: 227-34 [PMID:21429598]

Bylund DB et al. (1994) International Union of Pharmacology nomenclature of adrenoceptors. Pharmacol. Rev.46: 121-136 [PMID:7938162]

Cazzola M et al. (2011) β(2) -adrenoceptor agonists: current and future direction. Br. J. Pharmacol.163: 4-17 [PMID:21232045]

Daly CJ et al. (2011) Previously unsuspected widespread cellular and tissue distribution of β-adrenoceptors and its relevance to drug action. Trends Pharmacol. Sci.32: 219-26 [PMID:21429599]

Evans BA et al. (2010) Ligand-directed signalling at beta-adrenoceptors. Br. J. Pharmacol.159: 1022-38 [PMID:20132209]

Gilsbach R et al. (2012) Are the pharmacology and physiology of α_2 adrenoceptors determined by α_2-heteroreceptors and autoreceptors respectively? Br. J. Pharmacol.165: 90-102 [PMID:21658028]

Jensen BC et al. (2011) Alpha-1-adrenergic receptors: targets for agonist drugs to treat heart failure. J. Mol. Cell. Cardiol.51: 518-28 [PMID:21118696]

Kobilka BK. (2011) Structural insights into adrenergic receptor function and pharmacology. Trends Pharmacol. Sci.32: 213-8 [PMID:21414670]

Langer SZ. (2015) α2-Adrenoceptors in the treatment of major neuropsychiatric disorders. Trends Pharmacol. Sci.36: 196-202 [PMID:25771972]

McGrath JC. (2015) Localization of α-adrenoceptors: JR Vane Medal Lecture. Br. J. Pharmacol.172: 1179-94 [PMID:25377869]

Michel MC et al. (2011) Are there functional β_3-adrenoceptors in the human heart? Br. J. Pharmacol.162: 817-22 [PMID:20735409]

Michel MC et al. (2011) β-adrenoceptor agonist effects in experimental models of bladder dysfunction. Pharmacol. Ther.131: 40-9 [PMID:21510978]

Michel MC et al. (2015) Selectivity of pharmacological tools: implications for use in cell physiology. A review in the theme: Cell signaling: proteins, pathways and mechanisms. Am. J. Physiol., Cell Physiol.308: C505-20 [PMID:25631871]

Nishimune A et al. (2012) Phenotype pharmacology of lower urinary tract α(1)-adrenoceptors. Br. J. Pharmacol.165: 1226-34 [PMID:21745191]

Vasudevan NT et al. (2011) Regulation of β-adrenergic receptor function: an emphasis on receptor resensitization. Cell Cycle10: 3684-91 [PMID:22041711]

Walker JK et al. (2011) New perspectives regarding β(2) -adrenoceptor ligands in the treatment of asthma. Br. J. Pharmacol.163: 18-28 [PMID:21175591]Angiotensin receptors

Angiotensin receptors

Overview

The actions of angiotensin II (AGT, P01019) (Ang II) are mediated by AT1 and AT2 receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Angiotensin Receptors [2137]), which have around 30% sequence similarity. Endogenous ligands are angiotensin II(AGT, P01019) and angiotensin III(AGT, P01019) (Ang III), while angiotensin I(AGT, P01019) is weakly active in some systems.

NomenclatureAT1 receptorAT2 receptor
HGNC, UniProtAGTR1, P30556AGTR2, P50052
Selective agonistsL-162,313 (pIC50 7.8–7.9) [1490]CGP42112 (pIC50 9.6) [190], [p-aminoPhe6]ang II (pKd 9.1–9.4) [1789, 2139] – Rat
Antagoniststelmisartan (pIC50 8.4) [1241], olmesartan (pIC50 8.1) [981]
Selective antagonistscandesartan (pIC50 9.5–9.7) [1942], EXP3174 (pIC50 7.4–9.5) [1887, 1942], eprosartan (pIC50 8.4–8.8) [464], irbesartan (pIC50 8.7–8.8) [1942], losartan (pIC50 7.4–8.7) [1887, 2139], valsartan (pIC50 8.6) [2138], azilsartan (pIC50 8.1–8.1) [1551, 1844]PD123177 (pIC50 8.5–9.5) [291, 321, 450] – Rat, EMA401 (pIC50 8.5–9.3) [518, 1582, 1767], PD123319 (pKd 8.7–9.2) [449, 2025, 2139]
Labelled ligands[3H]A81988 (Antagonist) (pKd 9.2) [690] – Rat, [3H]L158809 (Antagonist) (pKd 9.2) [305] – Rat, [3H]eprosartan (Antagonist) (pKd 9.1) [21] – Rat, [3H]valsartan (Antagonist) (pIC50 8.8–9) [1954], [125I]EXP985 (Antagonist) (pKd 8.8) [322] – Rat, [3H]losartan (Antagonist) (pKd 8.2) [294] – Rat[125I]CGP42112 (Agonist) (pKd 10.6) [2017, 2018, 2139]

Comments

AT1 receptors are predominantly coupled to Gq/11, however they are also linked to arrestin recruitment and stimulate G protein-independent arrestin signalling [1156]. Most species express a single AGTR1 gene, but two related agtr1a and agtr1b 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. AT1 receptor antagonists bearing substituted 4-phenylquinoline moieties have been synthesized, which bind to AT1 receptors with nanomolar affinity and are slightly more potent than losartan in functional studies [264]. The antagonist activity of CGP42112 at the AT2 receptor has also been reported [2147].

The AT1 and bradykinin B2 receptors have been proposed to form a heterodimeric complex [3].

There is also evidence for an AT4 receptor that specifically binds angiotensin IV (AGT, P01019) and is located in the brain and kidney. An additional putative endogenous ligand for the AT4 receptor has been described (LVV-hemorphin(HBB, P68871), a globin decapeptide) [1296].

Further Reading

Ellis B et al. (2012) Evidence for a functional intracellular angiotensin system in the proximal tubule of the kidney. Am. J. Physiol. Regul. Integr. Comp. Physiol.302: R494-509 [PMID:22170616]

Karnik SS et al. (2015) International Union of Pharmacology. LXXXIX. Angiotensin Receptors: Interpreters of pathophysiological angiotensinergic stimuli. Pharmacological Reviews

MacKenzie A. (2011) Endothelium-derived vasoactive agents, AT1 receptors and inflammation. Pharmacol. Ther.131: 187-203 [PMID:21115037]

Patel BM et al. (2012) Aldosterone and angiotensin: Role in diabetes and cardiovascular diseases. Eur. J. Pharmacol.697: 1-12 [PMID:23041273]

Putnam K et al. (2012) The renin-angiotensin system: a target of and contributor to dyslipidemias, altered glucose homeostasis, and hypertension of the metabolic syndrome. Am. J. Physiol. Heart Circ. Physiol.302: H1219-30 [PMID:22227126]

Sevá Pessôa B et al. (2013) Key developments in renin-angiotensin-aldosterone system inhibition. Nat Rev Nephrol9: 26-36 [PMID:23165302]

Zhang H et al. (2015) Structure of the Angiotensin receptor revealed by serial femtosecond crystallography. Cell161: 833-44 [PMID:25913193]

de Gasparo M et al. (2000) International Union of Pharmacology. XXIII. The angiotensin II receptors. Pharmacol. Rev.52: 415-472 [PMID:10977869]

Apelin receptor

Overview

The apelin receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee on the apelin receptor [1510]) responds to apelin, a 36 amino-acid peptide derived initially from bovine stomach. Apelin-36(APLN, Q9ULZ1), apelin-13(APLN, Q9ULZ1) and [Pyr1]apelin-13(APLN, Q9ULZ1) are the predominant endogenous ligands which are cleaved from a 77 amino-acid precursor peptide (APLN, Q9ULZ1) by a so far unidentified enzymatic pathway [1864]. A second family of peptides discovered independently and named Elabela [323] or Toddler, that has little sequence similarity to apelin, has been proposed as a second endogenous apelin receptor ligand [1475].

Nomenclatureapelin receptor
HGNC, UniProtAPLNR, P35414
Rank order of potency[Pyr1]apelin-13 (APLN, Q9ULZ1) ≥apelin-13 (APLN, Q9ULZ1) >apelin-36 (APLN, Q9ULZ1) [503, 1864]
Endogenous agonistsapelin-13 (APLN, Q9ULZ1) (Selective) (pIC50 8.8–9.5) [503, 785, 1254], apelin receptor early endogenous ligand (APELA, P0DMC3) (Selective) (pKd 9.3) [412], apelin-17 (APLN, Q9ULZ1) (Selective) (pIC50 7.9–9) [468, 1254], [Pyr1]apelin-13 (APLN, Q9ULZ1) (Selective) (pIC50 7–8.8) [918, 1254], Elabela/Toddler-21 (APELA, P0DMC3) (pIC50 8.7) [2086], Elabela/Toddler-32 (APELA, P0DMC3) (pIC50 8.7) [2086], apelin-36 (APLN, Q9ULZ1) (Selective) (pIC50 8.2–8.6) [503, 785, 918, 1254], Elabela/Toddler-11 (APELA, P0DMC3) (pIC50 7.2) [2086]
Selective agonistsMM07 (Biased agonist) (pEC50 9.5) [203]
AntagonistsMM54 (pKi 8.2) [1166]
Labelled ligands[125I][Nle75,Tyr77]apelin-36 (human) (Agonist) (pKd 11.2) [918], [125I][Glp65Nle75,Tyr77]apelin-13 (Agonist) (pKd 10.7) [785], [125I](Pyr1)apelin-13 (Agonist) (pKd 9.5) [911], [125I]apelin-13 (Agonist) (pKd 9.2) [503], [3H](Pyr1)[Met(0)11]-apelin-13 (Agonist) (pKd 8.6) [1254]

Comments

Potency order determined for heterologously expressed human apelin receptor (pD2 values range from 9.5 to 8.6). The apelin receptor may also act as a co-receptor with CD4 for isolates of human immunodeficiency virus, with apelin blocking this function [279]. A modified apelin-13 peptide, apelin-13(F13A) was reported to block the hypotensive response to apelin in rat in vivo[1067], however, this peptide exhibits agonist activity in HEK293 cells stably expressing the recombinant apelin receptor [503].

Further Reading

Chandrasekaran B et al. (2008) The role of apelin in cardiovascular function and heart failure. Eur. J. Heart Fail.10: 725-32 [PMID:18583184]

Cheng B et al. (2012) Neuroprotection of apelin and its signaling pathway. Peptides37: 171-3 [PMID:22820556]

Davenport AP et al. (2007) Apelins. In Encyclopedic Reference of Molecular Pharmacology Edited by Offermanns S, Rosenthal W: Springer: 201-206

Japp AG et al. (2008) The apelin-APJ system in heart failure: pathophysiologic relevance and therapeutic potential. Biochem. Pharmacol.75: 1882-92 [PMID:18272138]

Langelaan DN et al. (2009) Structural insight into G-protein coupled receptor binding by apelin. Biochemistry48: 537-48 [PMID:19123778]

O'Carroll AM et al. (2013) The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis. J. Endocrinol.219: R13-35 [PMID:23943882]

Pitkin SL et al. (2010) International Union of Basic and Clinical Pharmacology. LXXIV. Apelin receptor nomenclature, distribution, pharmacology, and function. Pharmacol. Rev.62: 331-42 [PMID:20605969]

Yang P et al. (2015) Apelin, Elabela/Toddler, and biased agonists as novel therapeutic agents in the cardiovascular system. Trends Pharmacol. Sci.[PMID:26143239]

Bile acid receptor

Overview

The bile acid receptor (GPBA) responds to bile acids produced during the liver metabolism of cholesterol. Selective agonists are promising drugs for the treatment of metabolic disorders, such as type II diabetes, obesity and atherosclerosis.

NomenclatureGPBA receptor
HGNC, UniProtGPBAR1, Q8TDU6
Rank order of potencylithocholic acid>deoxycholic acid>chenodeoxycholic acid, cholic acid (Unknown) [917, 1214]
Selective agonistsbetulinic acid (pEC50 6) [590], oleanolic acid (pEC50 5.7) [1648]

Comments

The triterpenoid natural product betulinic acid has also been reported to inhibit inflammatory signalling through the NFκB pathway [1842]. Disruption of GPBA expression is reported to protect from cholesterol gallstone formation [1951]. A new series of 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carboxamides have been reported as highly potent agonists [1138].

Further Reading

Duboc H et al. (2014) The bile acid TGR5 membrane receptor: from basic research to clinical application. Dig Liver Dis46: 302-12 [PMID:24411485]

Fiorucci S et al. (2010) Bile acid-activated receptors in the treatment of dyslipidemia and related disorders. Prog. Lipid Res.49: 171-85 [PMID:19932133]

Fiorucci S et al. (2009) Bile-acid-activated receptors: targeting TGR5 and farnesoid-X-receptor in lipid and glucose disorders. Trends Pharmacol. Sci.30: 570-80 [PMID:19758712]

Keitel V et al. (2012) Perspective: TGR5 (Gpbar-1) in liver physiology and disease. Clin Res Hepatol Gastroenterol36: 412-9 [PMID:22521118]

Lefebvre P et al. (2009) Role of bile acids and bile acid receptors in metabolic regulation. Physiol. Rev.89: 147-91 [PMID:19126757]

Lieu T et al. (2014) GPBA: a GPCR for bile acids and an emerging therapeutic target for disorders of digestion and sensation. Br. J. Pharmacol.171: 1156-66 [PMID:24111923]

Pols TW et al. (2011) The bile acid membrane receptor TGR5 as an emerging target in metabolism and inflammation. J. Hepatol.54: 1263-72 [PMID:21145931]

Tiwari A et al. (2009) TGR5: an emerging bile acid G-protein-coupled receptor target for the potential treatment of metabolic disorders. Drug Discov. Today14: 523-30 [PMID:19429513]

Bombesin receptors

Overview

Bombesin receptors (nomenclature recommended by the NC-IUPHAR Subcommittee on bombesin receptors, [857]) are activated by the endogenous ligands gastrin-releasing peptide(GRP, P07492) (GRP), neuromedin B(NMB, P08949) (NMB) and GRP-(18-27)(GRP, P07492) (previously named neuromedin C). Bombesin is a tetradecapeptide, originally derived from amphibians, and is an agonist at BB1 and BB2 receptors. These receptors couple primarily to the Gq/11 family of G proteins (but see also [857]). Each of these receptors is widely distributed in the CNS and peripheral tissues [625, 857, 1556, 1642]. Activation of BB1 and BB2 receptors causes a wide range of physiological actions, including the stimulation of normal and neoplastic tissue growth, smooth-muscle contraction, appetite and feeding behavior, secretion and many central nervous system effects [857, 858, 859, 1185, 1317, 1556]. A physiological role for the BB3 receptor has yet to be fully defined although recently studies using receptor knockout mice and newly described agonists/antagonists suggest an important role in glucose and insulin regulation, metabolic homeostasis, feeding and other CNS behaviors and growth of normal/neoplastic tissues [625, 1186, 1430].

NomenclatureBB1 receptorBB2 receptorBB3 receptor
HGNC, UniProtNMBR, P28336GRPR, P30550BRS3, P32247
Endogenous agonistsneuromedin B (NMB, P08949) (Selective) (pKi 8.1–10.3) [857, 1556, 1919]neuromedin C (pIC50 9.9) [1919], gastrin releasing peptide(14-27) (human) (Selective) (pIC50 9.7–9.8) [1919]
Selective agonistscompound 8a [PMID: 24900283] (pIC50 8.9) [1129], compound 9g [PMID: 24412111] (pEC50 8.8) [1220], MK-7725 (pIC50 8.5) [324], MK-5046 (pKi 7.7–8.4) [1321, 1689], [D-Tyr6,Apa-4Cl11,Phe13,Nle14]bombesin-(6-14) (pKi 8.1) [1202], compound 17c [PMID: 25497965] (pEC50 7.9) [1219], compound 9f [PMID: 24412111] (pEC50 7.8) [1220], bag-1 (pIC50 7.7) [659], compound 22e [PMID: 20167483] (pIC50 7.6) [727], bag-2 (pIC50 7) [659]
AntagonistsD-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Nal-NH2 (pIC50 6.2–6.6) [624]
Selective antagonistsPD 176252 (pIC50 9.3–9.8) [624], PD 168368 (pIC50 9.3–9.6) [624], dNal-cyc(Cys-Tyr-dTrp-Orn-Val)-Nal-NH2[D-Phe6, Leu13, Cpa14,ψ13-14]bombesin-(6-14) (pKi 9.8) [624], JMV641 (pIC50 9.3) [1892] – Mouse, [(3-Ph-Pr6), His7,D-Ala11,D-Pro13,ψ13-14),Phe14] bombesin-(6-14) (pIC50 9.2) [624, 1062], [D-Tpi6, Leu13ψ(CH2NH)-Leu14]bombesin-(6-14) (pIC50 8.9) [624], Ac-GRP-(20-26)-methylester (pIC50 8.7) [624], JMV594 (pIC50 8.7–8.7) [1133, 1892] – Mousebantag-1 (pIC50 8.6–8.7) [659, 1321], ML-18 (pIC50 5.3) [1316]
Labelled ligands[125I]BH-NMB (human, mouse, rat) (Agonist), [125I][Tyr4]bombesin (Agonist)[125I][D-Tyr6]bombesin-(6-13)-methyl ester (Selective Antagonist) (pKd 9.3) [1201] – Mouse, [125I][Tyr4]bombesin (Agonist) (pKd 8.2) [131], [125I]GRP (human) (Agonist)[3H]bag-2 (Agonist) (pKd 8.6) [659] – Mouse, [125I][D-Tyr6,β-Ala11,Phe13,Nle14]bombesin-(6-14) (Agonist) (pKd 8–8.4) [1203, 1321]

Comments

All three subtypes may be activated by [D-Phe6,β-Ala11,Phe13,Nle14]bombesin-(6-14)[1203]. [D-Tyr6,Apa-4Cl11,Phe13,Nle14]bombesin-(6-14) has more than 200-fold selectivity for BB3 receptors over BB1 and BB2[1202].

Further Reading

Gonzalez N et al. (2008) Bombesin-related peptides and their receptors: recent advances in their role in physiology and disease states. Curr Opin Endocrinol Diabetes Obes15: 58-64 [PMID:18185064]

González N et al. (2015) Bombesin receptor subtype 3 as a potential target for obesity and diabetes. Expert Opin. Ther. Targets 1-18 [PMID:26066663]

Jensen RT et al. (2008) International Union of Pharmacology. LXVIII. Mammalian bombesin receptors: nomenclature, distribution, pharmacology, signaling, and functions in normal and disease states. Pharmacol. Rev.60: 1-42 [PMID:18055507]

Jensen RT et al. (2013) Bombesin-Related Peptides. In Handbook of Biologically Active Peptides. 2nd Revised edition. Edited by Kastin AJ: Elsevier: 1188-1196 [ISBN: 9780123850959]

Jensen RT et al. (2013) Bombesin Peptides (Cancer). In Handbook of Biologically Active Peptides. 2nd Revised edition. Edited by Kastin AJ: Elsevier: 506-511 [ISBN: 9780123850959]

Ladenheim EE.. (2013) Bombesin. In Handbook of Biologically Active Peptides. 2nd Revised edition. Edited by Kastin AJ: Elsevier: 1064-1070 [ISBN: 9780123850959]

Majumdar ID et al. (2011) Biology of mammalian bombesin-like peptides and their receptors. Curr Opin Endocrinol Diabetes Obes18: 68-74 [PMID:21042212]

Moody TW et al. (2015) Neuropeptides as lung cancer growth factors. Peptides[PMID:25836991]

Ramos-Álvarez I et al. (2015) Insights into bombesin receptors and ligands: Highlighting recent advances. Peptides[PMID:25976083]

Roesler R et al. (2012) Gastrin-releasing peptide receptors in the central nervous system: role in brain function and as a drug target. Front Endocrinol (Lausanne)3: 159 [PMID:23251133]

Sun YG et al. (2009) Cellular basis of itch sensation. Science325: 1531-4 [PMID:19661382]

Bradykinin receptors

Overview

Bradykinin (or kinin) receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Bradykinin (kinin) Receptors [1072]) are activated by the endogenous peptides bradykinin(KNG1, P01042) (BK), [des-Arg9]bradykinin(KNG1, P01042), Lys-BK (kallidin(KNG1, P01042)), [des-Arg10]kallidin(KNG1, P01042), T-kinin(KNG1, P01042) (Ile-Ser-BK), [Hyp3]bradykinin(KNG1, P01042) and Lys-[Hyp3]-bradykinin(KNG1, P01042). The variation in affinity or inactivity of B2 receptor antagonists could reflect the existence of species homologues of B2 receptors.

NomenclatureB1 receptorB2 receptor
HGNC, UniProtBDKRB1, P46663BDKRB2, P30411
Rank order of potency[des-Arg10]kallidin (KNG1, P01042) >[des-Arg9]bradykinin (KNG1, P01042) = kallidin (KNG1, P01042) >bradykinin (KNG1, P01042)kallidin (KNG1, P01042) >bradykinin (KNG1, P01042) ≫[des-Arg9]bradykinin (KNG1, P01042), [des-Arg10]kallidin (KNG1, P01042)
Endogenous agonists[des-Arg10]kallidin (KNG1, P01042) (Selective) (pKi 9.6–10) [69, 104, 876]
Selective agonists[Sar,D-Phe8,des-Arg9]bradykinin (pKi 5.7) [876][Hyp3,Tyr(Me)8]BK, [Phe8,ψ(CH2-NH)Arg9]BK
Antagonists[Leu9,des-Arg10]kallidin (pKi 9.1–9.3) [69, 104]
Selective antagonistsB-9958 (pKi 9.2–10.3) [596, 1570], R-914 (pA2 8.6) [617], R-715 (pA2 8.5) [618]icatibant (pKi 10.2) [39], FR173657 (pA2 8.2) [1593], anatibant (pKi 8.2) [1537]
Labelled ligands[125I]Hpp-desArg10HOE140 (pKd 10), [3H]Lys-[des-Arg9]BK (Agonist) (pKd 9.4), [3H]Lys-[Leu8][des-Arg9]BK (Antagonist)[3H]BK (human, mouse, rat) (Agonist) (pKd 9.4) [2034] – Mouse, [3H]NPC17731 (Antagonist) (pKd 9.1–9.4) [2119, 2120], [125I][Tyr8]bradykinin (Agonist)

Further Reading

Campos MM et al. (2006) Non-peptide antagonists for kinin B1 receptors: new insights into their therapeutic potential for the management of inflammation and pain. Trends Pharmacol. Sci.27: 646-51 [PMID:17056130]

Duchene J et al. (2009) The kinin B(1) receptor and inflammation: new therapeutic target for cardiovascular disease. Curr Opin Pharmacol9: 125-31 [PMID:19124274]

Marceau F et al. (2004) Bradykinin receptor ligands: therapeutic perspectives. Nat Rev Drug Discov3: 845-52 [PMID:15459675]

Paquet JL et al. (1999) Pharmacological characterization of the bradykinin B2 receptor: inter-species variability and dissociation between binding and functional responses. Br. J. Pharmacol.126: 1083-90 [PMID:10204994]

Thornton E et al. (2010) Kinin receptor antagonists as potential neuroprotective agents in central nervous system injury. Molecules15: 6598-618 [PMID:20877247]

Calcitonin receptors

Overview

This receptor family comprises a group of receptors for the calcitonin/CGRP family of peptides. The calcitonin (CT), amylin (AMY), calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on CGRP, AM, AMY, and CT receptors [721, 1528]) are generated by the genes CALCR (which codes for the CT receptor (CTR)) and CALCRL(which codes for the calcitonin receptor-like receptor, CLR, previously known as CRLR). Their function and pharmacology are altered in the presence of RAMPs (receptor activity-modifying proteins), which are single TM domain proteins of ca. 130 amino acids, identified as a family of three members; RAMP1, RAMP2 and RAMP3. There are splice variants of CTR; these in turn produce variants of the AMY receptor [1528], some of which can be potently activated by CGRP. The endogenous agonists are the peptides calcitonin(CALCA, P01258), α-CGRP(CALCA, P06881) (formerly known as CGRP-I), β-CGRP(CALCB, P10092) (formerly known as CGRP-II), amylin(IAPP, P10997) (occasionally called islet-amyloid polypeptide, diabetes-associated polypeptide), adrenomedullin(ADM, P35318) and adrenomedullin 2/intermedin (ADM2, Q7Z4H4). There are species differences in peptide sequences, particularly for the CTs. CTR-stimulating peptide {Pig} (CRSP) is another member of the family with selectivity for the CTR but it is not expressed in humans [907]. Olcegepant (also known as BIBN4096BS, pKi 10.5) and telcagepant(also known as MK0974, pKi 9) are the most selective antagonists available, having a high selectivity for CGRP receptors, with a particular preference for those of primate origin.

CLR by itself binds no known endogenous ligand, but in the presence of RAMPs it gives receptors for CGRP, adrenomedullin and adrenomedullin 2/intermedin.

NomenclatureCT receptorAMY1 receptorAMY2 receptorAMY3 receptor
HGNC, UniProtCALCR, P30988
SubunitsRAMP1 (Accessory protein), CT receptorCT receptor, RAMP2 (Accessory protein)CT receptor, RAMP3 (Accessory protein)
Rank order of potencycalcitonin (salmon)calcitonin (CALCA, P01258) ≥amylin (IAPP, P10997), α-CGRP (CALCA, P06881) >adrenomedullin (ADM, P35318), adrenomedullin 2/intermedin (ADM2, Q7Z4H4)calcitonin (salmon)amylin (IAPP, P10997) ≥α-CGRP (CALCA, P06881) >adrenomedullin 2/intermedin (ADM2, Q7Z4H4) ≥calcitonin (CALCA, P01258) >adrenomedullin (ADM, P35318)Poorly definedcalcitonin (salmon)amylin (IAPP, P10997) >α-CGRP (CALCA, P06881) ≥adrenomedullin 2/intermedin (ADM2, Q7Z4H4) ≥calcitonin (CALCA, P01258) >adrenomedullin (ADM, P35318)
Endogenous agonistscalcitonin (CALCA, P01258) (Selective) (pEC50 9–11.2) [32, 58, 718, 1027, 1087, 1341]amylin (IAPP, P10997) (pEC50 9–9.7) [610]amylin (IAPP, P10997) (pEC50 8.3–9.1) [610]amylin (IAPP, P10997) (pEC50 8.9–9.6) [610]
Labelled ligands[125I]CT (human) (Agonist) (pKd 9–10), [125I]CT (salmon) (Agonist) (pKd 10)[125I]BH-AMY (rat, mouse) (Agonist) (pKd 9–10)[125I]BH-AMY (rat, mouse) (Agonist) (pKd 9–10)[125I]BH-AMY (rat, mouse) (Agonist) (pKd 9–10)
Nomenclaturecalcitonin receptor-like receptorCGRP receptorAM1 receptorAM2 receptor
HGNC, UniProtCALCRL, Q16602
Subunitscalcitonin receptor-like receptor, RAMP1 (Accessory protein)calcitonin receptor-like receptor, RAMP2 (Accessory protein)calcitonin receptor-like receptor, RAMP3 (Accessory protein)
Rank order of potencyα-CGRP (CALCA, P06881) >adrenomedullin (ADM, P35318) ≥adrenomedullin 2/intermedin (ADM2, Q7Z4H4) >amylin (IAPP, P10997) ≥calcitonin (salmon)adrenomedullin (ADM, P35318) >adrenomedullin 2/intermedin (ADM2, Q7Z4H4) >α-CGRP (CALCA, P06881), amylin (IAPP, P10997) >calcitonin (salmon)adrenomedullin (ADM, P35318) ≥adrenomedullin 2/intermedin (ADM2, Q7Z4H4) ≥α-CGRP (CALCA, P06881) >amylin (IAPP, P10997) >calcitonin (salmon)
Endogenous agonistsβ-CGRP (CALCB, P10092) (pKi 9.9–11) [20, 1251], α-CGRP (CALCA, P06881) (pKi 9.7–10) [20, 1251]adrenomedullin (ADM, P35318) (pKi 8.3–9.2) [20, 1251]adrenomedullin (ADM, P35318) (pKi 8.3–9) [20, 539]
Antagonistsolcegepant (pKi 10.2–10.7) [435, 719, 720, 1194], telcagepant (pKi 9.1) [1633]
Selective antagonistsAM-(22-52) (human) (pKi 7–7.8) [20, 720, 1251]
Labelled ligands[125I]αCGRP (human) (Agonist) (pKd 10), [125I]αCGRP (mouse, rat) (Agonist)[125I]AM (rat) (Agonist) (pKd 10–9)[125I]AM (rat) (Agonist) (pKd 9–10)

Comments

It is important to note that a complication with the interpretation of pharmacological studies with AMY receptors in transfected cells is that most of this work has likely used a mixed population of receptors, encompassing RAMP-coupled CTR as well as CTR alone. This means that although in binding assays human calcitonin(CALCA, P01258) has low affinity for 125I-AMY binding sites, cells transfected with CTR and RAMPs can display potent CT functional responses. Transfection of human CTR with any RAMP can generate receptors with a high affinity for both salmon CT and AMY and varying affinity for different antagonists [337, 718, 719]. The major human CTR splice variant (hCT(a), which does not contain an insert) with RAMP1 (i.e. the AMY1(a) receptor) has a high affinity for CGRP, unlike hCT(a)-RAMP3 (i.e. AMY3(a) receptor) [337, 718]. However, the AMY receptor phenotype is RAMP-type, splice variant and cell-line-dependent [1886]. In particular, CGRP is a more potent agonist than amylin(IAPP, P10997) at increasing cAMP at the delta 47 hCT(a) receptor, when transfected with RAMP1 (to give the corresponding AMY1(a) receptor) in Cos 7 cells [1543].

The ligands described represent the best available but their selectivity is limited. For example, adrenomedullin has appreciable affinity for CGRP receptors. CGRP can show significant cross-reactivity at AMY receptors and AM2 receptors. Adrenomedullin 2/intermedin also has high affinity for the AM2 receptor [779]. CGRP-(8-37) acts as an antagonist of CGRP (pKi 8) and inhibits some AM and AMY responses (pKi 6-7). It is weak at CT receptors. Salmon CT-(8-32) is an antagonist at both AMY and CT receptors. AC187, a salmon CT analogue, is also an antagonist at AMY and CT receptors. Human AM-(22-52) has some selectivity towards AM receptors, but with modest potency (pKi  7), limiting its use [720]. AM-(22-52) is slightly more effective at AM1 than AM2 receptors but this difference is not sufficient for this peptide to be a useful discriminator of the AM receptor subtypes. Olcegepant shows the greatest selectivity between receptors but still has significant affinity for AMY1 receptors [1973].

Ligand responsiveness at CT and AMY receptors can be affected by receptor splice variation and can depend on the pathway being measured. 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 [1324, 1886].

Gs is a prominent route for effector coupling for CLR and CTR but other pathways (e.g. Ca2+, ERK, Akt), and G proteins can be activated [1972]. There is evidence that CGRP-RCP (a 148 amino-acid hydrophilic protein, ASL(P04424) is important for the coupling of CLR to adenylyl cyclase [498]. [125I]-Salmon CT is the most common radioligand for CT receptors but it has high affinity for AMY receptors and is also poorly reversible. [125I]-Tyr0-CGRP is widely used as a radioligand for CGRP receptors.

Some early literature distinguished between CGRP1 and CGRP2 receptors. It is now clear that the complex of CALCRL and RAMP1 represents the CGRP1 subtype and is now known simply as the CGRP receptor [721]. The CGRP2 receptor is now considered to have arisen from the actions of CGRP at AM2 and AMY receptors. This term should not be used [721].

Further Reading

Barwell J et al. (2012) Calcitonin and calcitonin receptor-like receptors: common themes with family B GPCRs? Br. J. Pharmacol.166: 51-65 [PMID:21649645]

Booe JM et al. (2015) Structural Basis for Receptor Activity-Modifying Protein-Dependent Selective Peptide Recognition by a G Protein-Coupled Receptor. Mol. Cell[PMID:25982113]

Hay DL et al. (2008) International Union of Pharmacology. LXIX. Status of the calcitonin gene-related peptide subtype 2 receptor. Pharmacol. Rev.60: 143-5 [PMID:18552275]

Hong Y et al. (2011) The pharmacology of Adrenomedullin 2/Intermedin. Br J Pharmacol[PMID:21658025]

Moore EL et al. (2011) Targeting a Family B GPCR/RAMP Receptor Complex: CGRP Receptor Antagonists and Migraine. Br J Pharmacol[PMID:21871019]

Poyner DR et al. (2002) International Union of Pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors. Pharmacol Rev.54: 233-246 [PMID:12037140]

Russo AF. (2015) Calcitonin gene-related peptide (CGRP): a new target for migraine. Annu. Rev. Pharmacol. Toxicol.55: 533-52 [PMID:25340934]

Calcium-sensing receptors

Overview

The calcium-sensing receptor (CaS, provisional nomenclature as recommended by NC-IUPHAR[530]) responds to extracellular calcium and magnesium in the millimolar range and to gadolinium and some polycations in the micromolar range [229]. The sensitivity of CaS to primary agonists can be increased by aromatic L-amino acids [362] and also by elevated extracellular pH [1544] or decreased extracellular ionic strength [1545]. This receptor bears no sequence or structural relation to the plant calcium receptor, also called CaS.

NomenclatureCaS receptorGPRC6 receptor
HGNC, UniProtCASR, P41180GPRC6A, Q5T6X5
Amino-acid rank order of potencyL-phenylalanine, L-tryptophan, L-histidine>L-alanine>L-serine, L-proline, L-glutamic acid>L-aspartic acid (not L-lysine, L-arginine, L-leucine and L-isoleucine) [362]
Cation rank order of potencyGd3+>Ca2+>Mg2+ [229]
Polyamine rank order of potencyspermine>spermidine>putrescine [1546]
Allosteric modulatorsAC265347 (Positive) (pEC50 7.6–8.1) [1160], NPS 2143 (Negative) (pIC50 7.1–7.4) [1377, 2087], cinacalcet (Positive) (pEC50 7.3) [1378], calindol (Positive) (pEC50 6.5) [1499], calindol (Positive) (pKd 6–6.5) [930], tecalcet (Positive) (pKd 6.5) [1379], calhex 231 (Negative) (pIC50 6.4) [1500]
Comments2-benzylpyrrolidine derivatives of NPS 2143 are also negative allosteric modulators of the calcium sensing receptor [2087]. etelcalcetide is a novel peptide agonist of the receptor [1975].GPRC6 is a related Gq-coupled receptor which responds to basic amino acids [2004].

Comments

Positive allosteric modulators of CaS are termed Type II calcimimetics and can suppress parathyroid hormone (PTH(PTH, P01270)) secretion [1379]. Negative allosteric modulators are called calcilytics and can act to increase PTH(PTH, P01270) secretion [1377].

The central role of CaS in the maintenance of extracellular calcium homeostasis is seen most clearly in patients with loss-of-function CaS mutations who develop familial hypocalciuric hypercalcaemia (heterozygous mutation) or neonatal severe hyperparathyroidism (homozygous mutation) and in CaS null mice [293, 765], which exhibit similar increases in PTH secretion and blood Ca2+ levels. A gain-of-function mutation in the CaS gene is associated with autosomal dominant hypocalcaemia.

Further Reading

Breitwieser GE. (2012) Minireview: the intimate link between calcium sensing receptor trafficking and signaling: implications for disorders of calcium homeostasis. Mol. Endocrinol.26: 1482-95 [PMID:22745192]

Brown EM. (2013) Role of the calcium-sensing receptor in extracellular calcium homeostasis. Best Pract. Res. Clin. Endocrinol. Metab.27: 333-43 [PMID:23856263]

Conigrave AD et al. (2013) Calcium-sensing receptor (CaSR): pharmacological properties and signaling pathways. Best Pract. Res. Clin. Endocrinol. Metab.27: 315-31 [PMID:23856262]

Magno AL et al. (2011) The calcium-sensing receptor: a molecular perspective. Endocr. Rev.32: 3-30 [PMID:20729338]

Nemeth EF et al. (2013) Calcimimetic and calcilytic drugs for treating bone and mineral-related disorders. Best Pract. Res. Clin. Endocrinol. Metab.27: 373-84 [PMID:23856266]

Wellendorph P et al. (2004) Molecular cloning, expression, and sequence analysis of GPRC6A, a novel family C G-protein-coupled receptor. Gene335: 37-46 [PMID:15194188]

Yarova PL et al. (2015) Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma. Sci Transl Med7: 284ra60 [PMID:25904744]

Cannabinoid receptors

Overview

Cannabinoid receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Cannabinoid Receptors [1494]) 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 of endogenous agonists at these receptors are complicated by the possibility of differential susceptibility of endogenous ligands to enzymatic conversion [35].

NomenclatureCB1 receptorCB2 receptor
HGNC, UniProtCNR1, P21554CNR2, P34972
(Sub)family-selective agonistsHU-210 (pKi 9.1–10.2) [509, 1733], CP55940 (pKi 8.3–9.2) [509, 1602, 1733], WIN55212-2 (pKi 6.9–8.7) [509, 1730, 1733], Δ9-tetrahydrocannabinol (Partial agonist) (pKi 7.3–7.4) [509, 1733]HU-210 (pKi 9.3–9.8) [509, 1579, 1733], WIN55212-2 (pKi 8.4–9.6) [509, 1730, 1733], CP55940 (pKi 8.6–9.2) [509, 1602, 1733], Δ9-tetrahydrocannabinol (Partial agonist) (pKi 7.1–7.5) [106, 509, 1579, 1733]
Selective agonistsarachidonyl-2-chloroethylamide (pKi 8.9) [755] – Rat, arachidonylcyclopropylamide (pKi 8.7) [755] – Rat, O-1812 (pKi 8.5) [420] – Rat, R-(+)-methanandamide (pKi 7.7) [931] – RatJWH-133 (pKi 8.5) [804, 1493], L-759,633 (pKi 7.7–8.2) [576, 1602], AM1241 (pKi 8.1) [2088], L-759,656 (pKi 7.7–7.9) [576, 1602], HU-308 (pKi 7.6) [699]
Selective antagonistsrimonabant (pKi 7.9–8.7) [508, 509, 1586, 1613, 1733], AM251 (pKi 8.1) [1038] – Rat, AM281 (pKi 7.9) [1037] – Rat, LY320135 (pKi 6.9) [508]SR144528 (pKi 8.3–9.2) [1587, 1602], AM-630 (pKi 7.5) [1602]
Labelled ligands[3H]rimonabant (Antagonist) (pKd 8.9–10) [205, 761, 889, 1498, 1588, 1742, 1873] – Rat

Comments

Both CB1 and CB2 receptors may be labelled with [3H]CP55940(0.5 nM; [1733]) and [3H]WIN55212-2(2-2.4 nM; [1756, 1783]). Anandamide is also an agonist at vanilloid receptors (TRPV1) and PPARs[1418, 2135]. There is evidence for an allosteric site on the CB1 receptor [1532]. All of the compounds listed as antagonists behave as inverse agonists in some bioassay systems [1494]. Moreover, GPR18, GPR55 and GPR119, although showing little structural similarity to CB1 and CB2receptors, respond to endogenous agents that are structurally similar to the endogenous cannabinoid ligands [1494].

Further Reading

Alexander SP et al. (2007) The complications of promiscuity: endocannabinoid action and metabolism. Br. J. Pharmacol.152: 602-23 [PMID:17876303]

Di Marzo V et al. (2007) Endocannabinoids and the regulation of their levels in health and disease. Curr. Opin. Lipidol.18: 129-40 [PMID:17353660]

Howlett AC et al. (2011) Endocannabinoid tone versus constitutive activity of cannabinoid receptors. Br. J. Pharmacol.163: 1329-43 [PMID:21545414]

McPartland JM et al. (2007) Meta-analysis of cannabinoid ligand binding affinity and receptor distribution: interspecies differences. Br. J. Pharmacol.152: 583-93 [PMID:17641667]

Mechoulam R et al. (2013) The endocannabinoid system and the brain. Annu Rev Psychol64: 21-47 [PMID:22804774]

O'Sullivan SE. (2007) Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors. Br. J. Pharmacol.152: 576-82 [PMID:17704824]

Pertwee RG et al. (2010) International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB_1 and CB_2. Pharmacol. Rev.62: 588-631 [PMID:21079038]

Ross RA. (2011) L-α-lysophosphatidylinositol meets GPR55: a deadly relationship. Trends Pharmacol. Sci.32: 265-9 [PMID:21367464]

Chemerin receptor

Overview

The chemerin receptor (nomenclature as recommended by NC-IUPHAR[396]) is activated by chemerin [1148, 1253, 2108] and the lipid-derived, anti-inflammatory ligand resolvin E1 (RvE1), which is the result of sequential metabolism of EPA by aspirin-modified cyclooxygenase and lipoxygenase [56, 57]. In addition, two GPCRs for resolvin D1 (RvD1) have been identified, FPR2/ALX, the lipoxin A4 receptor, and GPR32, an orphan receptor [1006].

Nomenclaturechemerin receptor
HGNC, UniProtCMKLR1, Q99788
Rank order of potencyresolvin E1>chemerin C-terminal peptide>18R-HEPE>EPA [56]
Selective agonistsresolvin E1
Labelled ligands[3H]resolvin E1 (Agonist) (pKd 8) [56, 57]

Chemokine receptors

Overview

Chemokine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Chemokine Receptors [78, 1346, 1347]) comprise a large subfamily of 7TM proteins that bind one or more chemokines, a large family of small cytokines typically possessing chemotactic activity for leukocytes. Chemokine receptors can be divided by function into two main groups: G protein-coupled chemokine receptors, which mediate leukocyte trafficking, and “Atypical chemokine receptors”, which may signal through non-G protein-coupled mechanisms and act as chemokine scavengers to downregulate inflammation or shape chemokine gradients [78].

Chemokines in turn can be divided by structure into four subclasses by the number and arrangement of conserved cysteines. CC (also known as β-chemokines; n= 28), CXC (also known as α-chemokines; n= 17) 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. G protein-coupled chemokine receptors are named acccording to the class of chemokines bound, whereas ACKR is the root acronym for atypical chemokine receptors [79]. Listed are those human agonists with EC50 values <50 nM in either Ca2+ flux or chemotaxis assays at human recombinant G protein-coupled chemokine 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 microbial non-chemokine ligands have also been identified for chemokine receptors. Many chemokine receptors function as HIV co-receptors, but CCR5 is the only one demonstrated to play an essential role in HIV/AIDS pathogenesis. The tables include both standard chemokine receptor names [2101] and the most commonly used aliases. Numerical data quoted are typically pKi or pIC50 values from radioligand binding to heterologously expressed receptors.

NomenclatureCCR1CCR2CCR3
HGNC, UniProtCCR1, P32246CCR2, P41597CCR3, P51677
Endogenous agonistsCCL3 (CCL3, P10147) (pKi 7.8–10.2) [328, 357, 747, 2134], CCL23 (CCL23, P55773) (Selective) (pKi 8.9) [328], CCL5 (CCL5, P13501) (pKi 6.8–8.2) [357, 747], CCL7 (CCL7, P80098) (pKi 8.1) [328, 667], CCL15 (CCL15, Q16663) (Selective) (pIC50 7.9) [373], CCL14 (CCL14, Q16627) (pKi 7.4) [328], CCL13 (CCL13, Q99616), CCL8 (CCL8, P80075)CCL2 (CCL2, P13500) (pIC50 9.3–10.2) [373, 1159, 1291, 1465, 1920], CCL13 (CCL13, Q99616) (pIC50 8.6–8.7) [1159, 1920], CCL7 (CCL7, P80098) (pIC50 8.4–8.7) [373, 1159, 1920], CCL11 (CCL11, P51671) (Partial agonist) (pIC50 7.1–7.7) [1159, 1465], CCL16 (CCL16, O15467)CCL13 (CCL13, Q99616) (pIC50 8.7–10.3) [1332, 1920], CCL24 (CCL24, O00175) (Selective) (pIC50 8–9.4) [1332, 1465], CCL5 (CCL5, P13501) (pKi 8.5–9.3) [391], CCL7 (CCL7, P80098) (pKi 8.6–9.2) [391], CCL11 (CCL11, P51671) (Selective) (pIC50 8.7–9) [452, 961, 1332, 1625, 1920], CCL26 (CCL26, Q9Y258) (Selective) (pIC50 7.9–8.9) [961, 1332, 1465], CCL15 (CCL15, Q16663) (pIC50 8.6) [373], CCL28 (CCL28, Q9NRJ3), CCL8 (CCL8, P80075)
AgonistsCCL11 {Mouse} (pKi 9.5–10) [391]
Endogenous antagonistsCCL4 (CCL4, P13236) (Selective) (pKi 7.1–7.8) [328, 357]CCL26 (CCL26, Q9Y258) (Selective) (pIC50 8.5) [1465]CXCL10 (CXCL10, P02778) (Selective), CXCL11 (CXCL11, O14625) (Selective), CXCL9 (CXCL9, Q07325) (Selective)
Antagonists
Selective antagonistsBX 471 (pKi 8.2–9) [1098], compound 2b-1 [PMID: 12614873] (pIC50 8.7) [1368], CP-481,715 (pKd 8) [614], UCB35625 (pIC50 8) [1625]GSK Compound 34 (pKi 7.6)banyu (I) (Inverse agonist) (pKi 8.5) [1977], SB328437 (pKi 8.4), BMS compound 87b (pKi 8.1) [1964]
Antibodies
Labelled ligands[125I]CCL7 (human) (Agonist) (pKd 9.2) [127], [125I]CCL3 (human) (Agonist) (pKd 8–8.8) [127, 623, 1646], [125I]CCL5 (human) (Agonist) (pKd 8.2) [1646][125I]CCL2 (human) (Agonist), [125I]CCL7 (human) (Agonist)[125I]CCL11 (human) (Antagonist) (pKd 8.3) [1977], [125I]CCL5 (human) (Agonist), [125I]CCL7 (human) (Agonist)
NomenclatureCCR4CCR5
HGNC, UniProtCCR4, P51679CCR5, P51681
Endogenous agonistsCCL22 (CCL22, O00626) (Selective) (pIC50 9.2) [822], CCL17 (CCL17, Q92583) (Selective) (pIC50 8.7) [822]CCL5 (CCL5, P13501) (pKi 9.2–9.7) [75, 1364, 1611], CCL4 (CCL4, P13236) (Selective) (pKi 9.4–9.6) [1364, 1611], CCL8 (CCL8, P80075) (pKi 9.3) [1611], CCL3 (CCL3, P10147) (pKi 8–8.9) [1364, 1611, 2134], CCL11 (CCL11, P51671) (pIC50 7.7) [157], CCL2 (CCL2, P13500) (pKi 7.5) [1364], CCL14 (CCL14, Q16627) (pKi 7.2) [1364], CCL16 (CCL16, O15467)
AgonistsvMIP-IIIR5-HIV-1 gp120
Endogenous antagonistsCCL7 (CCL7, P80098) (Selective) (pKi 7.5) [1364]
Antagonistsvicriviroc (pKi 9.1) [1805], ancriviroc (pKi 7.8–8.7) [1173, 1455, 1805]
Selective antagonistsE913 (pIC50 8.7) [1174], aplaviroc (pKi 8.5) [1173], maraviroc (pIC50 8.1) [1364], TAK-779 (pKi 7.5) [1173], MRK-1 [1023] – Rat
Antibodiesmogamulizumab (Inhibition) [51, 1731]
Labelled ligands[125I]CCL17 (human) (Agonist), [125I]CCL27 (human) (Agonist)[125I]CCL4 (human) (Agonist) (pKd 9.6) [1364], [125I]CCL3 (human) (Agonist), [125I]CCL5 (human) (Agonist), [125I]CCL8 (human) (Agonist)
NomenclatureCCR6CCR7CCR8CCR9CCR10
HGNC, UniProtCCR6, P51684CCR7, P32248CCR8, P51685CCR9, P51686CCR10, P46092
Endogenous agonistsCCL20 (CCL20, P78556) (pIC50 7.9–8.5) [18, 74, 1526], beta-defensin 4A (DEFB4ADEFB4B, O15263) (Selective) [2081]CCL21 (CCL21, O00585) (Selective) (pIC50 9.3) [2099], CCL19 (CCL19, Q99731) (Selective) (pIC50 7.7–9, median 8.6) [1449, 2098, 2099]CCL1 (CCL1, P22362) (Selective) (pIC50 8.5–9.8) [387, 710, 824], CCL8 {Mouse} – MouseCCL25 (CCL25, O15444) (Selective)CCL27 (CCL27, Q9Y4X3) (Selective), CCL28 (CCL28, Q9NRJ3) (Selective)
AgonistsvMIP-I (pIC50 8.9–9.9) [387, 824]
Selective antagonistsvMCC-I (pIC50 9.4) [387]
Labelled ligands[125I]CCL20 (human) (Agonist) (pKd∼10) [641][125I]CCL19 (human) (Agonist), [125I]CCL21 (human) (Agonist) [856][125I]CCL1 (human) (Agonist) (pKd 8.9–9.7) [824, 1597][125I]CCL25 (human) (Agonist)
NomenclatureCXCR1CXCR2CXCR3
HGNC, UniProtCXCR1, P25024CXCR2, P25025CXCR3, P49682
Endogenous agonistsCXCL8 (CXCL8, P10145) (pKi 8.8–9.5) [142, 675, 1068, 2032, 2049], CXCL6 (CXCL6, P80162) (pKi 7) [2053]CXCL1 (CXCL1, P09341) (Selective) (pKi 8.4–9.7) [675, 1068, 2049], CXCL8 (CXCL8, P10145) (pKi 8.8–9.5) [142, 675, 1068, 2032, 2049], CXCL7 (PPBP, P02775) (Selective) (pIC50 6.3–9.3) [16], CXCL3 (CXCL3, P19876) (Selective) (pIC50 7.8–9.2) [16], CXCL2 (CXCL2, P19875) (Selective) (pIC50 7–9.1) [16], CXCL5 (CXCL5, P42830) (Selective) (pIC50 6.9–9) [16], CXCL6 (CXCL6, P80162) (pKd 7) [2053]CXCL11 (CXCL11, O14625) (Selective) (pKi 10.4–10.5) [734], CXCL10 (CXCL10, P02778) (Selective) (pKi 7.8–9.8) [734, 2006], CXCL9 (CXCL9, Q07325) (Selective) (pKi 7.3–8.3) [734, 2006]
AgonistsvCXCL1 (pIC50 7.4) [1158], HIV-1 matrix protein p17 (pKd 5.7) [602]vCXCL1 (pIC50 8.2) [1158], HIV-1 matrix protein p17 (pKd 6.9) [602]
Selective agonists
Endogenous antagonistsCCL11 (CCL11, P51671) (Selective) (pKi 7.2) [2006], CCL7 (CCL7, P80098) (Selective) (pKi 6.6) [2006]
Antagonists
Selective antagonistsnavarixin (pIC50 10.3) [78, 456], danirixin (pIC50 7.9) [1285], SB 225002 (pIC50 7.7) [2016], elubirixin (pIC50 7.7) [78], SX-517 (pIC50 7.2) [1172]
Allosteric modulatorsreparixin (Negative) (pIC50 9) [142]reparixin (Negative) (pIC50 6.4) [142]
Labelled ligands[125I]CXCL8 (human) (Agonist) (pKd 8.9–9.6) [675, 1584][125I]CXCL8 (human) (Agonist) (pKd 9–9.4) [675, 1584], [125I]CXCL1 (human) (Agonist), [125I]CXCL5 (human) (Agonist), [125I]CXCL7 (human) (Agonist)[125I]CXCL10 (human) (Agonist), [125I]CXCL11 (human) (Agonist)
CommentsReports on the expression of native CXCR1 by mouse leukocytes are not conclusive. There are reports on the existence of mouse Cxcr1 and on Cxcr1 knockout mice, but the distinct function of the gene and of its knockout phenotype are unclear [118, 351, 1297, 1628, 1794].
NomenclatureCXCR4CXCR5CXCR6
HGNC, UniProtCXCR4, P61073CXCR5, P32302CXCR6, O00574
Endogenous agonistsCXCL12α (CXCL12, P48061) (Selective) (pKd 7.7–8.2) [746, 1136], CXCL12β (CXCL12, P48061) (Selective) (pKd 7.9) [746]CXCL13 (CXCL13, O43927) (Selective) (pKd 7.3) [97]CXCL16 (CXCL16, Q9H2A7) (Selective) (pKd 9) [2026]
Agonists 
Selective agonistsALX40-4C (Partial agonist) (pIC50 6.1) [2121], X4-HIV-1 gp120 
Endogenous antagonists 
Antagonistsplerixafor (pKi 7) [2121] 
Selective antagonistsT134 (pIC50 8.4) [1856], AMD070 (pIC50 7.9) [1750], HIV-Tat 
Allosteric modulators 
Labelled ligands[125I]CXCL12α (human) (Agonist) (pKd 8.1–8.4) [421, 746][125I]CXCL13 (mouse) (Agonist) [222] – Mouse[125I]CXCL16 (human) (Agonist)
Comments
NomenclatureCX3CR1XCR1ACKR1ACKR2
HGNC, UniProtCX3CR1, P49238XCR1, P46094ACKR1, Q16570ACKR2, O00590
Endogenous ligandsCXCL5 (CXCL5, P42830), CXCL6 (CXCL6, P80162), CXCL8 (CXCL8, P10145), CXCL11 (CXCL11, O14625), CCL2 (CCL2, P13500), CCL5 (CCL5, P13501), CCL7 (CCL7, P80098), CCL11 (CCL11, P51671), CCL14 (CCL14, Q16627), CCL17 (CCL17, Q92583)CCL2 (CCL2, P13500), CCL3 (CCL3, P10147), CCL4 (CCL4, P13236), CCL5 (CCL5, P13501), CCL7 (CCL7, P80098), CCL8 (CCL8, P80075), CCL11 (CCL11, P51671), CCL13 (CCL13, Q99616), CCL14 (CCL14, Q16627), CCL17 (CCL17, Q92583), CCL22 (CCL22, O00626)
Endogenous agonistsCX3CL1 (CX3CL1, P78423) (Selective) (pIC50 8.9) [577]XCL1 (XCL1, P47992) (Selective), XCL2 (XCL2, Q9UBD3) (Selective)
Labelled ligands[125I]CX3CL1 (human) (Agonist) 
CommentsWhen fused with secreted alkaline phophatase (SEAP), XCL1 functions as a probe at XCR1ACKR1 is used by Plasmodium vivax and Plasmodium knowlsei for entering erythrocytes. 
NomenclatureACKR3ACKR4CCRL2
HGNC, UniProtACKR3, P25106ACKR4, Q9NPB9CCRL2, O00421
Endogenous ligandschemerin C-terminal peptide, CCL19 (CCL19, Q99731) [95]
Endogenous agonistsCXCL12α (CXCL12, P48061) (pEC50 7.5–7.9) [640, 1785], CXCL11 (CXCL11, O14625), adrenomedullin {Mouse} [965] – MouseCCL19 (CCL19, Q99731) (pKi 8.4) [1997], CCL25 (CCL25, O15444) (pKi 7.6) [1997], CCL21 (CCL21, O00585) (pKi 6.9) [1997]

Comments

Mouse Cxcr binds iodinated mouse KC (CXCL1{Mouse}) and mouse MIP-2 (CXCL2{Mouse}) with high affinity (mouse KC and MIP-2 are homologues of human CXCL1(CXCL1, P09341), CXCL2(CXCL2, P19875) and CXCL3(CXCL3, P19876)), but shows low affinity for human IL-8 (CXCL8(CXCL8, P10145)).

Specific chemokine receptors facilitate cell entry by microbes, such as ACKR1 for Plasmodium vivax, and CCR5 for HIV-1. Virally encoded chemokine receptors are known (e.g. US28, a homologue of CCR1 from human cytomegalovirus and ORF74, which encodes a homolog of CXCR2 in Herpesvirus saimiri and Herpesvirus-68), 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(CCL1, P22362)), MCP-1 (CCL2(CCL2, P13500)), MIP-1α(CCL3(CCL3, P10147)), MIP-1β(CCL4(CCL4, P13236)), RANTES (CCL5(CCL5, P13501)), MCP-3 (CCL7(CCL7, P80098)), MCP-2 (CCL8(CCL8, P80075)), eotaxin (CCL11(CCL11, P51671)), MCP-4 (CCL13(CCL13, Q99616)), HCC-1 (CCL14(CCL14, Q16627)), Lkn-1/HCC-2 (CCL15(CCL15, Q16663)), TARC (CCL17(CCL17, Q92583)), ELC (CCL19(CCL19, Q99731)), LARC (CCL20(CCL20, P78556)), SLC (CCL21(CCL21, O00585)), MDC (CCL22(CCL22, O00626)), MPIF-1 (CCL23(CCL23, P55773)), eotaxin-2 (CCL24(CCL24, O00175)), TECK (CCL25(CCL25, O15444)), eotaxin (CCL26(CCL26, Q9Y258)), eskine/CTACK (CCL27(CCL27, Q9Y4X3)) and MEC (CCL28(CCL28, Q9NRJ3)). The CXC chemokine family (CXCL1-17) includes GROα(CXCL1(CXCL1, P09341)), GROβ(CXCL2(CXCL2, P19875)), GROγ(CXCL3(CXCL3, P19876)), platelet factor 4 (CXCL4(PF4, P02776)), ENA78 (CXCL5(CXCL5, P42830)), GCP-2 (CXCL6(CXCL6, P80162)), NAP-2 (CXCL7(PPBP, P02775)), IL-8 (CXCL8(CXCL8, P10145)), MIG (CXCL9(CXCL9, Q07325)), IP10 (CXCL10(CXCL10, P02778)), I-TAC (CXCL11(CXCL11, O14625)), SDF-1 (CXCL12, i.e.CXCL12α(CXCL12, P48061) and CXCL12β(CXCL12, P48061)), BLC (CXCL13(CXCL13, O43927)), BRAK (CXCL14(CXCL14, O95715)), mouse lungkine (CXCL15 {Mouse}) SR-PSOX (CXCL16(CXCL16, Q9H2A7)) and CXCL17(CXCL17, Q6UXB2). The CX3C chemokine (CX3CL1(CX3CL1, P78423)) is also known as fractalkine (neurotactin in the mouse). Like CXCL16(CXCL16, Q9H2A7), and unlike other chemokines, CX3CL1(CX3CL1, P78423) 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(XCL1, P47992)) is also known as lymphotactin.

Two chemokine receptor antagonists have now been approved by the FDA: the CCR5 antagonist maraviroc (Pfizer) for treatment of HIV/AIDS in patients with CCR5-using strains; and the CXCR4 antagonist plerixafor (Sanofi) for hematopoietic stem cell mobilization with G-CSF(CSF3, P09919) in patients undergoing transplantation in the context of chemotherapy for lymphoma and multiple myeloma.

Further Reading

Bachelerie F et al. (2015) An atypical addition to the chemokine receptor nomenclature: IUPHAR Review ~15~. Br. J. Pharmacol.[PMID:25958743]

Koelink PJ et al. (2012) Targeting chemokine receptors in chronic inflammatory diseases: an extensive review. Pharmacol. Ther.133: 1-18 [PMID:21839114]

Murphy PM. (2002) International Union of Pharmacology. XXX. Update on chemokine receptor nomenclature. Pharmacol. Rev.54: 227-9 [PMID:12037138]

Murphy PM et al. (2000) International Union of Pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacol. Rev.52: 145-176 [PMID:10699158]

Muñoz LM et al. (2011) Receptor oligomerization: a pivotal mechanism for regulating chemokine function. Pharmacol. Ther.131: 351-8 [PMID:21600920]

Scholten DJ et al. (2012) Pharmacological modulation of chemokine receptor function. Br. J. Pharmacol.165: 1617-43 [PMID:21699506]

Szpakowska M et al. (2012) Function, diversity and therapeutic potential of the N-terminal domain of human chemokine receptors. Biochem. Pharmacol.84: 1366-80 [PMID:22935450]

White GE et al. (2013) CC chemokine receptors and chronic inflammation–therapeutic opportunities and pharmacological challenges. Pharmacol. Rev.65: 47-89 [PMID:23300131]

Cholecystokinin receptors

Overview

Cholecystokinin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on CCK receptors [1403]) are activated by the endogenous peptides cholecystokinin-8 (CCK-8(CCK, P06307)), CCK-33(CCK, P06307), CCK-58(CCK, P06307) and gastrin (gastrin-17(GAST, P01350)). There are only two distinct subtypes of CCK receptors, CCK1 and CCK2 receptors [992, 1986], with some alternatively spliced forms most often identified in neoplastic cells. The CCK receptor subtypes are distinguished by their peptide selectivity, with the CCK1 receptor requiring the carboxyl-terminal heptapeptide-amide that includes a sulfated tyrosine for high affinity and potency, while the CCK2 receptor requires only the carboxyl-terminal tetrapeptide shared by both CCK and gastrin peptides. These receptors have characteristic and distinct distributions, with both present in both the central nervous system and peripheral tissues.

NomenclatureCCK1 receptorCCK2 receptor
HGNC, UniProtCCKAR, P32238CCKBR, P32239
Rank order of potencyCCK-8 (CCK, P06307) ≫gastrin-17 (GAST, P01350), desulfated cholecystokinin-8>CCK-4 (CCK, P06307)CCK-8 (CCK, P06307) ≥gastrin-17 (GAST, P01350), desulfated cholecystokinin-8, CCK-4 (CCK, P06307)
Endogenous agonistsdesulfated cholecystokinin-8 (pIC50 8.3–8.7) [1071], gastrin-17 (GAST, P01350) (Selective) (pIC50 8.3) [805] – Mouse, CCK-4 (CCK, P06307) (pIC50 7.5) [832], desulfated gastrin-14 (GAST, P01350), desulfated gastrin-17 (GAST, P01350), desulfated gastrin-34 (GAST, P01350), desulfated gastrin-71 (GAST, P01350), gastrin-14 (GAST, P01350), gastrin-34 (GAST, P01350), gastrin-71 (GAST, P01350)
Selective agonistsA-71623 (pIC50 8.4) [63] – Rat, JMV180 (pIC50 8.3) [926], GW-5823 (pIC50 7.6) [737]RB-400 (pKi 9.1) [123] – Rat, PBC-264 (pIC50 9.1) [844] – Rat
Antagonistslintitript (pIC50 8.3) [632]
Selective antagonistsdevazepide (pIC50 9.7) [805] – Rat, T-0632 (pIC50 9.6) [1861] – Rat, PD-140548 (pIC50 8.6) [1748] – Rat, lorglumide (pIC50 6.7–8.2) [805, 834] – RatYF-476 (pIC50 9.7) [196, 1854], GV150013 (pIC50 9.4) [1930], L-740093 (pIC50 9.2) [1398], YM-022 (pIC50 9.2) [1398], JNJ-26070109 (pIC50 8.5) [1336], L-365260 (pIC50 8.4) [1071], RP73870 (pIC50 8) [1115] – Rat, LY262691 (pIC50 7.5) [1561] – Rat
Labelled ligands[3H]devazepide (Antagonist) (pKd 9.7) [292], [125I]DTyr-Gly-[(Nle28,31)CCK-26-33 (Agonist) (pIC50 9) [1527][3H]PD140376 (Antagonist) (pKi 9.7–10) [809] – Guinea pig, [125I]PD142308 (Antagonist) (pKd 9.6) [781] – Guinea pig, [125I]DTyr-Gly-[(Nle28,31)CCK-26-33 (Agonist) (pIC50 9) [1527], [125I]gastrin (Agonist) (pIC50 9), [3H]gastrin (Agonist) (pIC50 9), [3H]L365260 (Antagonist) (pKd 8.2–8.5) [1398], [125I]-BDZ2 (Antagonist) (pKi 8.4) [25]

Comments

While a cancer-specific CCK receptor has been postulated to exist, which also might be responsive to incompletely processed forms of CCK (Gly-extended forms), this has never been isolated. An alternatively spliced form of the CCK2 receptor in which intron 4 is retained, adding 69 amino acids to the intracellular loop 3 (ICL3) region, has been described to be present particularly in certain neoplasms where mRNA mis-splicing has been commonly observed [1764], but it is not clear that this receptor splice form plays a special role in carcinogenesis. Another alternative splicing event for the CCK2 receptor was reported [1782], with alternative donor sites in exon 4 resulting in long (452 amino acids) and short (447 amino acids) forms of the receptor differing by five residues in ICL3, however, no clear functional differences have been observed.

Further Reading

Cawston EE et al. (2010) Therapeutic potential for novel drugs targeting the type 1 cholecystokinin receptor. Br. J. Pharmacol.159: 1009-21 [PMID:19922535]

Dockray GJ. (2009) Cholecystokinin and gut-brain signalling. Regul. Pept.155: 6-10 [PMID:19345244]

Dufresne M et al. (2006) Cholecystokinin and gastrin receptors. Physiol. Rev.86: 805-47 [PMID:16816139]

Miller LJ et al. (2008) Structural basis of cholecystokinin receptor binding and regulation. Pharmacol. Ther.119: 83-95 [PMID:18558433]

Class Frizzled GPCRs

Overview

Receptors of the Class Frizzled (FZD, nomenclature as agreed by the NC-IUPHAR subcommittee on the Class Frizzled GPCRs [1676]), are GPCRs originally identified inDrosophila [285], which are highly conserved across species. FZDs are activated by WNTs, which are cysteine-rich lipoglycoproteins 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 regulator β-catenin(CTNNB1, P35222) or being β-catenin-independent (often referred to as canonical vs. non-canonical WNT/FZD signalling, respectively). WNT stimulation of FZDs can, in cooperation with the low density lipoprotein receptors LRP5 (O75197) and LRP6(O75581), lead to the inhibition of a constitutively active destruction complex, which results in the accumulation of β-catenin and subsequently its translocation to the nucleus. β-Catenin, in turn, modifies gene transcription by interacting with TCF/LEF transcription factors. β-Catenin-independent FZD signalling is far more complex with regard to the diversity of the activated pathways. WNT/FZD signalling can lead to the activation of pertussis toxin-sensitive heterotrimeric G proteins [939], the elevation of intracellular calcium [1757], activation of cGMP-specific PDE6 [17] and elevation of cAMP as well as RAC-1, JNK, Rho and Rho kinase signalling [695]. Furthermore, the phosphoprotein Disheveled constitutes a key player in WNT/FZD signalling. As with other GPCRs, members of the Frizzled family are functionally dependent on the arrestin scaffolding protein for internalization [306], as well as for β-catenin-dependent [235] and -independent [236, 940] signalling. The pattern of cell signalling is complicated by the presence of additional ligands, which can enhance or inhibit FZD signalling (secreted Frizzled-related proteins (sFRP), Wnt-inhibitory factor(WIF1, Q9Y5W5) (WIF), sclerostin(SOST, Q9BQB4) or Dickkopf (DKK)), as well as modulatory (co)-receptors with Ryk, ROR1, ROR2 and Kremen, which may also function as independent signalling proteins.

NomenclatureSMO
HGNC, UniProtSMO, Q99835
Antagonistssaridegib (pIC50 8.9) [1904], glasdegib (pIC50 8.3) [1342], erismodegib (pKi 8.2) [1979]
Selective antagonistsvismodegib (pKi 7.8) [1979]

Comments

There is limited knowledge about WNT/FZD specificity and which molecular entities determine the signalling outcome of a specific WNT/FZD pair. Understanding of the coupling to G proteins is incomplete (see [423]). There is also a scarcity of information on basic pharmacological characteristics of FZDs, such as binding constants, ligand specificity or concentration-response relationships [937].

Ligands associated with FZD signalling

WNTs: Wnt-1(WNT1, P04628), Wnt-2(WNT2, P09544) (also known as Int-1-related protein), Wnt-2b(WNT2B, Q93097) (also known as WNT-13), Wnt-3(WNT3, P56703) , Wnt-3a(WNT3A, P56704), Wnt-4(WNT4, P56705), Wnt-5a(WNT5A, P41221) , Wnt-5b(WNT5B, Q9H1J7), Wnt-6(WNT6, Q9Y6F9), Wnt-7a(WNT7A, O00755), Wnt-7b(WNT7B, P56706), Wnt-8a(WNT8A, Q9H1J5), Wnt-8b(WNT8B, Q93098), Wnt-9a(WNT9A, O14904) (also known as WNT-14), Wnt-9b(WNT9B, O14905) (also known as WNT-15 or WNT-14b), Wnt-10a(WNT10A, Q9GZT5), Wnt-10b(WNT10B, O00744) (also known as WNT-12), Wnt-11(WNT11, O96014) and Wnt-16(WNT16, Q9UBV4).

Extracellular proteins that interact with FZDs:norrin(NDP, Q00604), R-spondin-1(RSPO1, Q2MKA7), R-spondin-2(RSPO2, Q6UXX9) , R-spondin-3(RSPO3, Q9BXY4), R-spondin-4(RSPO4, Q2I0M5), sFRP-1(SFRP1, Q8N474), sFRP-2(SFRP2, Q96HF1), sFRP-3(FRZB, Q92765), sFRP-4(SFRP4, Q6FHJ7), sFRP-5(SFRP5, Q6FHJ7).

Extracellular proteins that interact with WNTs or LRPs:Dickkopf 1(DKK1, O94907), WIF1 (Q9Y5W5), sclerostin(SOST, Q9BQB4), kremen 1(KREMEN1, Q96MU8) and kremen 2 (KREMEN2, Q8NCW0)

Small exogenous ligands: Foxy-5 [1835], Box-5, UM206 [1031], and XWnt8 (P28026) also known as mini-Wnt8.

Further Reading

Dijksterhuis JP et al. (2013) WNT/Frizzled signaling: receptor-ligand selectivity with focus on FZD-G protein signaling and its physiological relevance. Br J Pharmacol[PMID:24032637]

King TD et al. (2012) The Wnt/β-catenin signaling pathway: a potential therapeutic target in the treatment of triple negative breast cancer. J. Cell. Biochem.113: 13-8 [PMID:21898546]

King TD et al. (2012) Frizzled7 as an emerging target for cancer therapy. Cell. Signal.24: 846-51 [PMID:22182510]

Koval A et al. (2011) Yellow submarine of the Wnt/Frizzled signaling: submerging from the G protein harbor to the targets. Biochem. Pharmacol.82: 1311-9 [PMID:21689640]

Schuijers J et al. (2012) Adult mammalian stem cells: the role of Wnt, Lgr5 and R-spondins. EMBO J.31: 2685-96 [PMID:22617424]

Schulte G. (2010) International Union of Basic and Clinical Pharmacology. LXXX. The class Frizzled receptors. Pharmacol. Rev.62: 632-67 [PMID:21079039]

Schulte G et al. (2010) beta-Arrestins - scaffolds and signalling elements essential for WNT/Frizzled signalling pathways? Br. J. Pharmacol.159: 1051-8 [PMID:19888962]

Complement peptide receptors

Overview

Complement peptide receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Complement peptide receptors [