Ion Channels

Authors

  • S P H Alexander,

  • A Mathie,

  • J A Peters


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

Acid-sensing (proton-gated) (ASICs)

Overview: Acid-sensing ion channels (ASICs, provisional nomenclature; see Wemmie et al., 2006; Lingueglia et al., 2007) are members of a Na+ channel superfamily that includes the epithelial Na channel (ENaC), the FMRF-amide activated channel (FaNaC) of invertebrates, the degenerins (DEG) of Caenorhabitis elegans, channels in Drosophila melanogaster and ‘orphan’ channels that include BLINaC (Sakai et al., 1999) and INaC (Schaefer et al. (2000). ASIC subunits contain two putative TM domains and assemble as homo- or hetero-trimers (Jasti et al., 2007) to form proton-gated, voltage-insensitive, Na+ permeable, channels. Splice variants of ASIC1 [provisionally termed ASIC1a (ASIC, ASICα, BNaC2α) (Waldmann et al. 1997a), ASIC1b (ASICβ, BNaC2β) (Chen et al., 1998) and ASIC1b2 (ASICβ2) (Ugawa et al., 2001); note that ASIC1a is also permeable to Ca2+] and ASIC2 [provisionally termed ASIC2a (MDEG1, BNaC1α, BNC1a) (Price et al., 1996; Waldmann et al., 1996; Garcia-Anoveros et al., 1997) and ASIC2b (MDEG2, BNaC1β) (Lingueglia et al., 1997)] have been cloned. Unlike ASIC2a (listed in table), heterologous expression of ASIC2b alone does not support H+-gated currents. A third member, ASIC3 (DRASIC, TNaC1) (Waldmann et al., 1997b), has been identified. Transcripts encoding a fourth mammalian member of the acid-sensing ion channel family (ASIC4/SPASIC) do not produce a proton-gated channel in heterologous expression systems (Akopian et al., 2000; Grunder et al., 2000), whereas one zebrafish orthologue (zASIC4.1) is functional as a homomer (Paukert et al., 2004) but a second (zASIC4.2) is not (Chen et al., 2007). ASIC channels are expressed in central and peripheral neurons including nociceptors where they participate in neuronal sensitivity to acidosis. The activation of ASIC1a within the brain contributes to neuronal injury caused by focal ischemia (Xiong et al., 2007). Further proposed roles for centrally and peripherally located ASICs are reviewed in Wemmie et al. (2006) and Lingueglia (2007). The relationship of the cloned ASICs to endogenously expressed proton-gated ion channels is becoming established (Escoubas et al., 2000; Sutherland et al., 2001; Wemmie et al., 2002, 2003, 2006; Lingueglia et al., 2006; 2007, Diochot et al., 2004, 2007). Heterologously expressed heteromultimers form ion channels with altered kinetics, ion selectivity, pH- sensitivity and sensitivity to blockers (Lingueglia et al., 1997; Babinski et al., 2000, Escoubas et al., 2000) that resemble some of the native proton activated currents recorded from neurones.

NomenclatureASIC1ASIC2ASIC3
Other namesASIC; BNaC2BNC1; BNaC1; MDEGDRASIC, TNaC1
Ensembl IDENSG00000110881ENSG00000108684OTTHUMG00000023710
Endogenous activatorsExtracellular H+ (ASIC1a, pEC50 ∼ 6.2-6.8; ASIC1b, pEC50 ∼ 5.1-6.2)Extracellular H+ (pEC50 ∼ 4.1-5.0)Extracellular H+ (transient component pEC50 ∼ 6.2-6.7) (sustained component pEC50 ∼ 3.5-4.3)
Blockers (IC50)ASIC1a: Psalmotoxin 1 (PcTx1) (0.9 nM), Zn2+ (7 ∼ nM), Pb2+ (∼ 4 μM), Ni2+ (∼ 0.6 mM), amiloride (10 μM), EIPA, benzamil (10 μM), ibuprofen/flurbiprofen (350 μM), ASIC1b: Amiloride (21-23 μM); Pb2+ (∼ 1.5 μM)Amiloride (28 μM), Cd2+ (∼ 1 mM)APETx2 (63 nM) (transient component only), amiloride (16-63 μM) (transient component only—sustained component enhanced by 200 μM amiloride), aspirin/diclofenac (92 μM—sustained component), salicylic acid (260 μM—sustained component), Gd3+ 40 μM
Functional characteristicsASIC1a: γ ∼ 14pS; PNa/PK = 5-13, PNa/PCa = 2.5; rapid activation rate (5.8-13.7 ms) rapid inactivation rate (1.2-4 s) @ pH 6.0 ASIC1b: PNa/Pk = 14.0; PNageqslant R: gt-or-equal, slanted PCa; rapid activation rate (9.9 ms); rapid inactivation rate (0.9-1.7 s) @ pH 6.0γ ∼ 10.4-13.4 pS; PNa/PK = 10, PNa/PCa = 20; rapid activation rate, moderate inactivation rate (3.3-5.5 s) @ pH 5γ ∼ 13-15 pS; biphasic response consisting of rapidly inactivating transient and sustained components; very rapid activation (<5 ms) and inactivation (0.4 s); transient component partially inactivated at pH 7.2
Probes[125I]-PcTx1 (ASIC1a KD = 213 pM)  

Psalmotoxin 1 (PcTx1) inhibits ASIC1a by modifying activation and desensitization by H+, but has little effect upon ASIC1b, ASIC2a, ASIC3, or ASIC1a expressed as a heteromultimer with either ASIC2a, or ASIC3 (Escoubas et al., 2000; Diochot et al., 2007). Blockade of ASIC1a by PcTx1 results in the activation of the endogenous enkephalin pathway and has very potent analgesic effects in rodents (Mazzuca et al., 2007). APETx2 most potently blocks homomeric ASIC3 channels, but also ASIC2b + ASIC3, ASIC1b + ASIC3, and ASIC1a + ASIC3 heteromeric channels with IC50 values of 117 nM, 900 nM and 2 μM, respectively. APETx2 has no effect on ASIC1a, ASIC1b, ASIC2a, or ASIC2a + ASIC3 (Diochot et al., 2004, 2007). A-317567 blocks ASIC channels native to dorsal root ganglion neurones with an IC50 within the range 2-30 μM (Dube et al., 2005). The pEC50 values for proton activation of ASIC channels are influenced by numerous factors including extracellular di- and poly-valent ions, Zn2+, protein kinase C and serine proteases (Lingueglia et al., 2006). Rapid acidification is required for activation of ASIC1 and ASIC3 due to fast inactivation/desensitization. pEC50 values for H+-activation of either transient, or sustained, currents mediated by ASIC3 vary in the literature and may reflect species and/or methodological differences (Waldmann et al., 1997b; de Weille et al., 1998; Babinski et al., 1999). The transient and sustained current components mediated by rASIC3 are selective for Na+ (Waldmann et al., 1997b); for hASIC3 the transient component is Na+ selective (PNa/PK>10) whereas the sustained current appears non-selective (PNa/PK = 1.6) (de Weille et al., 1998; Babinski et al., 1999). Nonsteroidal anti-inflammatory drugs (NSAIDs) are direct blockers of ASIC currents within the therapeutic range of concentrations (reviewed by Voilley, 2004). ASIC1a is blocked by flurbiprofen and ibuprofen and currents mediated by ASIC3 are inhibited by salicylic acid, aspirin and diclofenac. Extracellular Zn2+ potentiates proton activation of homomeric and heteromeric channels incorporating ASIC2a, but not homomeric ASIC1a or ASIC3 channels (Baron et al., 2001). However, removal of contaminating Zn2+ by chealation reveals a high affinity block of homomeric ASIC1a and heteromeric ASIC1a + ASIC2 channels by Zn2+ indicating complex biphasic actions of the divalent (Chu et al., 2004). Ammonium activates ASIC channels (most likely ASIC1a) in midbrain dopaminergic neurones which may be relevant to neuronal disorders that are associated with hyperammonemia (Pidoplichko and Dani, 2006). The positive modulation of homomeric, heteromeric and native ASIC channels by the peptide FMRFamide and related substances, such as neuropeptides FF and SF, is reviewed in detail by Lingueglia et al. (2006). Inflammatory conditions and particular pro-inflammatory mediators induce overexpression of ASIC-encoding genes, enhance ASIC currents (Mamet et al., 2002), and in the case of arachidonic acid directly activate the channel (Smith et al., 2007).

Abbreviations: A-317567, C-{6-[2-(1-Isopropyl-2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-cyclopropyl]-naphthalen-2-yl}-methanediamine; EIPA, ethylisopropylamiloride; FMRFamide, Phe-Met-Arg-Phe-amide; Neuropeptide FF, Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-amide; Neuropeptide SF, Ser-Leu-Ala-Pro-Gln-Arg-Phe-amide

Further Reading

Diochot S, Salinas M, Baron A, Escoubas P, Lazdunski M (2007). Peptides inhibitors of acid-sensing ion channels. Toxicon49: 271–284.

Kress M, Waldmann R (2006). Acid sensing ionic channels. Curr Top Membr57: 241–276.

Krishtal O (2003). The ASICs: Signaling molecules? Modulators? Trends Neurosci26: 477–483.

Lingueglia E (2007). Acid-sensing ion channels in sensory perception. J Biol Chem282: 17325–17329.

Lingueglia E, Deval E, Lazdunski M (2006). FMRFamide-gated sodium channel and ASIC channels: a new class of ionotropic receptors for FMRFamide and related peptides. Peptides27: 1138–1152.

Reeh PW, Kress M (2001). Molecular physiology of proton transduction in nociceptors. Curr Opin Pharmacol1: 45–51.

Sutherland SP, Cook SP, McCleskey EW (2000). Chemical mediators of pain due to tissue damage and ischemia. Prog Brain Res129: 21–38.

Voilley N (2004). Acid-sensing ion channels (ASICs): new targets for the analgesic effects of non-steroid anti-inflammatory drugs (NSAIDs). Curr Drug Targets Inflamm Allerg3: 71–79.

Waldmann R (2001). Proton-gated cation channels-neuronal acid sensors in the central and peripheral nervous system. Adv Exp Med Biol502: 293–304.

Waldmann R, Lazdunski M (1998). H+-gated cation channels: neuronal acid sensors in the NaC/DEG family of ion channels. Curr Opin Neurobiol8: 418–424.

Wemmie JA, Price MP, Welsh MJ (2006). Acid-sensing ion channels: advances, questions and therapeutic opportunities. Trends Neurosci29: 578–586.

Xiong ZG, Chu XP, Simon RP (2007). Acid sensing ion channels-novel therapeutic targets for ischemic brain injury. Front Biosci12: 1376–1386.

Xiong ZG, Pignataro G, Li M, Chang SY, Simon RP (2007). Acid-sensing ion channels as pharmacological targets for neurodegenerative diseases. Curr Opin Pharmacol Oct 16 [E-pub ahead of print].

Xu TL, Xiong ZG (2007). Dynamic regulation of acid-sensing ion channels by extracellular and intracellular modulators. Curr Med Chem14: 1753–1763.

References

Akopian AN et al. (2000). Neuroreport11: 2217–2222.

Babinski K et al. (1999). J Neurochem72: 51–57.

Babinski K et al. (2000). J Biol Chem37: 28519–28525.

Baron A et al. (2001). J Biol Chem276: 35361–35367.

Chen C-C et al. (1998). Proc Natl Acad Sci USA95: 10240–10245.

Chen X et al. (2007). J Biol Chem282: 30406–30416.

Chu X-P et al. (2004). J Neurosci24: 8678–8689.

De Weille JR et al. (1998). FEBS Lett433: 257–260.

Diochot S et al. (2004). EMBO J23: 1516–1525.

Dube GR et al. (2005). Pain117: 88–96.

Escoubas P et al. (2000). J Biol Chem275: 25116–25121.

Garcia-Anoveros J et al. (1997). Proc Natl Acad Sci USA94: 1459–1464.

Grunder S et al. (2000). Neuroreport11: 1607–1611.

Jasti J et al. (2007). Nature449: 316–323.

Lingueglia E et al. (1997). J Biol Chem272: 29778–29783.

Mamet J et al. (2002). J Neurosci22: 10662–10670.

Mazzuca M et al. (2007). Nat Neurosci10: 943–945.

Paukert M et al. (2004). J Biol Chem279: 18733–18791.

Pidoplichko VI, Dani JA (2006). Proc Natl Acad Sci USA103: 11376–11380.

Price MP et al. (1996). J Biol Chem271: 7879–7882.

Sakai H et al. (1999). J Physiol (Lond)519: 323–333.

Schaefer L et al. (2000). FEBS Lett471: 205–210.

Smith ES et al. (2007). Neuroscience145: 686–698.

Sutherland SP et al. (2001). Proc Natl Acad Sci USA98: 711–716.

Ugawa S et al. (2001). Neuroreport12: 2865–2869.

Waldmann R et al. (1996). J Biol Chem271: 10433–10436.

Waldmann R et al. (1997a). Nature386: 173–177.

Waldmann R et al. (1997b). J Biol Chem272: 20975–20978.

Wemmie JA et al. (2002). Neuron34: 463–477.

Wemmie JA et al. (2003). J Neurosci23: 5496–5502.

Citation Information

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

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

Aquaporins

Overview: Aquaporins and aquaglyceroporins are membrane channels that allow the permeation of water and certain other small solutes across the cell membrane. Since the isolation and cloning of the first aquaporin (AQP1) (Preston et al., 1992), 12 additional members of the family have been identified, although little is known about the functional properties of two of these (AQP11 (ENSG00000178301) and AQP12 (ENSG00000184945)). The other 11 aquaporins can be divided into two families (aquaporins and aquaglyceroporins) depending on whether they are permeable to glycerol (King et al., 2004). One or more members of this family of proteins have been found to be expressed in almost all tissues of the body. Individual AQP subunits have six transmembrane domains with an inverted symmetry between the first three and last three domains (Castle, 2005). Functional AQPs exist as tetramers but, unusually, each subunit contains a separate pore, so each channel has four pores.

NomenclatureAQP0AQP1AQP2AQP3
Ensembl IDENSG00000135517ENSG00000106125ENSG00000167580ENSG00000165272
ActivatorscGMP
InhibitorsHg2+Hg2+, TEA, Ag+Hg2+Hg,2+ acid pH
PermeabilityWater (low)Water (high)Water (high)Water (high), glycerol
NomenclatureAQP4AQP5AQP6AQP7
Ensembl IDENSG00000171885ENSG00000161798ENSG00000086159ENSG00000165269
ActivatorsAcid pH
InhibitorsPKC activationHg2+Hg2+Hg2+
PermeabilityWater (high)Water (high)Water (low), anionsWater (high), glycerol
NomenclatureAQP8AQP9AQP10
Ensembl IDENSG00000103375ENSG00000103569ENSG00000143595
Activators
InhibitorsHg2+Hg2+, phloretinHg2+
PermeabilityWater (high)Water (low), glycerolWater (low), glycerol

AQP6 is an intracellular channel permeable to anions as well as water (Yasui et al., 1999).

Further Reading

Agre P (2006). The aquaporin water channels. Proc Am Thoroc Soc3: 5–13.

Agre P, King LS, Yasui M, Guggino WB, Ottersen OP, Fujiyoshi Y et al. (2002). Aquaporin water channels: from atomic structure to clinical medicine. J Physiol542: 3–16.

Amiry-Moghaddam M, Ottersen OP (2003). The molecular basis of water transport in the brain. Nat Rev Neurosci4: 991–1001.

Castle NA (2005). Aquaporins as targets for drug discovery. Drug Discov Today10: 485–493.

De Groot BL, Grubmuller H (2005). The dynamics and energetics of water permeation and proton exclusion in aquaporins. Curr Opin Struct Biol15: 176–183.

Frigeri A, Nicchia GP, Svelto M (2007). Aquaporins as targets for drug discovery. Curr Pharm Des13: 2421–2427.

Jeyaseelan K, Sepramaniam S, Armugam A, Wintour EM (2006). Aquaporins: a promising target for drug development. Expert Opin Ther Targets10: 889–909.

Kimelberg HK (2004). Water homeostasis in the brain: basic concepts. Neuroscience129: 851–860.

King KL, Kozono D, Agre P (2004). From structure to disease: the evolving tale of aquaporin biology. Nat Rev Mol Cell Biol5: 687–698.

Wang F, Feng XC, Li YM, Yang H, Ma TH (2006). Aquaporins as potential drug targets. Acta Pharmacol Sin27: 395–401.

References

Preston GM et al. (1992). Science256: 385–387.

Yasui M et al. (1999). Nature402: 184–187.

Citation Information

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

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

Calcium (voltage-gated)

Overview: Calcium (Ca2+) channels are voltage-gated ion channels present in the membrane of most excitable cells. The nomenclature for Ca2+ channels was proposed by Ertel et al. (2000) and approved by the NC-IUPHAR subcommittee on Ca2+ channels (Catterall et al., 2005). Ca2+ channels form hetero-oligomeric complexes. The α1 subunit is pore-forming and provides the extracellular binding site(s) for practically all agonists and antagonists. The 10 cloned α-subunits can be grouped into three families: (1) the high-voltage activated dihydropyridine-sensitive (L-type, Cav1.x) channels; (2) the high-voltage activated dihydropyridine-insensitive (Cav2.x) channels and (3) the low-voltage-activated (T-type, Cav3.x) channels. Each α1 subunit has four homologous repeats (I-IV), each repeat having six transmembrane domains and a pore-forming region between transmembrane domains S5 and S6. Gating is thought to be associated with the membrane-spanning S4 segment, which contains highly conserved positive charges. Many of the α1-subunit genes give rise to alternatively spliced products. At least for high-voltage activated channels, it is likely that native channels comprise co-assemblies of α1, β and α2-δ subunits. The γ subunits have not been proven to associate with channels other than α1 s. The α2-δ1 and α2-δ2 subunits bind gabapentin and pregabalin.

NomenclatureCav1.1Cav1.2Cav1.3Cav1.4Cav2.1
Alternative namesL-type, α1S, skeletal muscle LL-type, α1C, cardiac or smooth muscle LL-type, α1DL-type, α1FP-type, Q-type, α1a
Ensembl IDENSG00000081248ENSG00000151067ENSG00000157388ENSG00000102001ENSG00000141837
Activators(—)-(S)-BayK8644 SZ(+)-(S)-202-791 FPL64176(—)-(S)-BayK8644 SZ(+)-(S)-202-791 FPL64176(—)-(S)-BayK8644(—)-(S)-BayK8644 
BlockersDihydropyridine antagonists, e.g. nifedipine, diltiazem, verapamil, calciseptineDihydropyridine antagonists, e.g. nifedipine diltiazem, verapamil, calciseptineLess sensitive to dihydropyridine antagonists verapamilLess sensitive to dihydropyridine antagonistsω-Agatoxin IVA (P: IC50 ∼ 1 nM) (Q: IC50 ∼ 90 nM) ω-Agatoxin IVB, ω-Conotoxin, MVIIC
Functional characteristicsHigh voltage-activated, slow inactivationHigh voltage-activated, slow inactivation (Ca2+ dependent)Low-moderate voltage-activated, slow inactivation (Ca2+ dependent)Moderate voltage-activated, slow inactivation (Ca2+ independent)Moderate voltage-activated, moderate inactivation
NomenclatureCav2.2Cav2.3Cav3.1Cav3.2Cav3.3
Alternative namesN-type, α1BR-type, α1ET-type, α1GT-type, α1HT-type, α1I
Ensembl IDENSG00000148408ENSG00000198216ENSG00000006283ENSG00000196557ENSG00000100346
Blockersω-Conotoxin GVIA, ω-Conotoxin MVIICSNX482 (may not be completely specific), high Ni2+Mibefradil, low sens. to Ni2+, kurtoxin, SB-209712Mibefradil, high sens. to Ni2+, kurtoxin, SB-209712Mibefradil, low sens. to Ni2+, kurtoxin, SB-209712
Functional characteristicsHigh voltage-activated, moderate inactivationModerate voltage-activated, fast inactivationLow voltage-activated, fast inactivationLow voltage-activated, fast inactivationLow voltage-activated, moderate inactivation

In many cell types, P and Q current components cannot be adequately separated and many researchers in the field have adopted the terminology ‘P/Q-type’ current when referring to either component.

Abbreviations: FPL64176, 2,5-dimethyl-4-[2(phenylmethyl)benzoyl]-H-pyrrole-3-carboxylate; SB-209712, (1,6,bis{1-[4-(3-phenylpropyl)piper-idinyl]}hexane); (—)-(S)-BAYK8664, (—)-(S)-methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluromethylphenyl)-pyridine-5-carboxylate; SNX482, 41 amino acid peptide-(GVDKAGCRYMFGGCSVNDDCCPRLGCHSLFSYCAWDLTFSD); SZ(+)-(S)-202-791, isopropyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-5-nitro-3-pyridinecarboxylate

Further Reading

Catterall WA (2000). Structure and regulation of voltage-gated Ca2+ channels. Annu Rev Cell Dev Biol16: 521–555.

Catterall WA, Perez-Reyes E, Snutch TP, Striessing J (2005). International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels. Pharmacol Rev57: 411–425.

Davies A, Hendrich J, Van Minh AT, Wratten J, Douglas L, Dolphin AC (2007). Functional biology of the alpha(2)delta subunits of voltage-gated calcium channels. Trends Pharmacol Sci28: 220–228.

Dolphin AC (2003). G protein modulation of voltage-gated calcium channels. Pharmacol Rev55: 607–627.

Elmslie KS (2004). Calcium channel blockers in the treatment of disease. J Neurosci Res75: 733–741.

Ertel EA, Campbell KP, Harpold MM, Hofmann F, Mori Y, Perez-Reyes E et al. (2000). Nomenclature of voltage-gated calcium channels. Neuron25: 533–535.

Hofmann F, Lacinova L, Klugbauer N (1999). Voltage-dependent calcium channels; from structure to function. Rev Physiol Biochem Pharmacol139: 35–87.

Kochegarov AA (2003). Pharmacological modulators of voltage-gated calcium channels and their therapeutic application. Cell Calcium33: 145–162.

Lewis RJ, Garcia ML (2003). Therapeutic potential of venom peptides. Nat Rev Drug Discov2: 790–802.

Lory P, Chemin J (2007). Towards the discovery of novel T-type calcium channel blockers. Expert Opin Ther Targets11: 717–722.

Nelson MT, Todorovic SM, Perez-Reyes E (2006). The role of T-type calcium channels in epilepsy and pain. Curr Pharm Des12: 2189–2197.

Perez-Reyes E (2003). Molecular physiology of low-voltage-activated T-type calcium channels. Physiol Rev83: 117–161.

Taylor CP, Anelotti T, Fauman E (2007). Pharmacology and mechanism of action of pregabalin; the calcium channel alpha2-delta subunit as a target for antiepileptic drug discovery. Epilepsy Res73: 137–150.

Terlau H, Olivera BM (2004). Conus venoms: a rich source of novel ion channel-targeted peptides. Physiol Rev84: 41–68.

Triggle DJ (2006). L-type calcium channels. Curr Pharm Des12: 443–457.

Triggle DJ (2007). Calcium channel antagonists: clinical uses - past, present and future. Biochem Pharmacol74: 1–9.

Trimmer JS, Rhodes KJ (2004). Localisation of voltage-gated ion channels in mammalian brain. Annu Rev Physiol66: 477–519.

Yu FH, Catterall WA (2004). The VGL-chanome: a protein superfamily specialized for electrical signaling and ionic homeostasis. Sci STKE2004 (253): re15.

Citation Information

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

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

CatSper

Overview: CatSper channels (CatSper1-4; nomenclature as agreed by NC-IUPHAR, Clapham and Garbers, 2005) are putative 6TM, voltage-gated, calcium permeant channels that are presumed to assemble as a tetramer of α-like subunits and mediate the current ICatSper. In mammals, CatSper subunits are structurally most closely related to individual domains of voltage-activated calcium channels (Cav) (Ren et al., 2001). CatSper1 (Ren et al., 2001), CatSper2 (Quill et al., 2001) and CatSpers 3 and 4 (Lobley et al., 2003; Lin et al., 2005; Qi et al., 2007), in common with a recently identified putative 2TM auxiliary CatSperβ protein (Liu et al., 2007), are restricted to the testis and localised to the principle piece of sperm tail.

NomenclatureCatSper1CatSper2CatSper3CatSper4
Ensembl IDENSG00000175294ENSG00000166762ENSG00000152705ENSG00000188782
ActivatorsConstitutively active, weakly facilitated by membrane depolarisation, strongly augmented by intracellular alkalinisation
BlockersCd2+ (200 μM), Ni2+ (300 μM), ruthenium red (10 μM)
Functional characteristicsCalcium selective ion channel (Ba2+ > Ca2+geqslant R: gt-or-equal, slanted Mg2+geqslant R: gt-or-equal, slanted Na+); quasilinear monovalent cation current in the absence of extracellular divalent cations; alkalinization shifts the voltage-dependence of activation towards negative potentials (V1/2 @ pH 6.0= +87 mV; V1/2 @ pH 7.5= + 11 mV)Required for ICatSperRequired for ICatSperRequired for ICatSper

CatSper channel subunits expressed singly, or in combination, fail to functionally express in heterologous expression systems (Quill et al., 2001; Ren et al., 2001). The properties of CatSper1 tabulated above are derived from whole cell voltage-clamp recordings comparing currents endogenous to spermatozoa isolated from the corpus epididymis of wild-type and Catsper1(-/-) mice (Kirichok et al., 2006). ICatSper is also undetectable in the spermatozoa of Catsper2(-/-), Catsper3(-/-), or Catsper4(-/-) mice and CatSper 1 associates with CatSper 2, 3, or 4 in heterologous expression systems (Qi et al., 2007). Moreover, targeted disruption of Catsper1, 2, 3, or 4 genes results in an identical phenotype in which spermatozoa fail to exhibit the hyperactive movement (whip-like flagellar beats) necessary for penetration of the egg cumulus and zona pellucida and subsequent fertilization. Such disruptions are associated with a deficit in alkalinization and depolarization-evoked Ca2+ entry into spermatozoa (Carlson et al., 2003, 2005; Qi et al., 2007). Thus, it is likely that the CatSper pore is formed by a heterotetramer of CatSpers1-4 (Qi et al., 2007). The driving force for Ca2+ entry is principally determined by a mildly outwardly rectifying K+ channel (KSper) that, like CatSpers, is activated by intracellular alkalinization (Navarro et al., 2007). KSper is not yet identified, but its properties are most consistent with mSlo3, a protein detected only in testis (Navarro et al., 2007).

Further Reading

Clapham DE, Garbers DL (2005). International Union of Pharmacology. L. Nomenclature and structure-function relationships of CatSper and two-pore channels. Pharmacol Rev57: 451–454.

Quill TA, Wang D, Garbers DL (2006). Insights into sperm cell motility through sNHE and the CatSpers. Mol Cell Endocrinol250: 84–92.

Zhang D, Gopalakrishnan M (2005). Sperm ion channels: molecular targets for the next generation of contraceptive medicines? J Androl26: 643–653.

References

Carlson AE et al. (2005). J Biol Chem280: 32238–32244.

Carlson AE et al. (2003). Proc Natl Acad Sci USA100: 14864–14868.

Kirichok Y et al. (2006). Nature439: 737–740.

Lin J-L et al. (2005). Biol Reprod73: 1235–1242.

Liu J et al. (2007). J Biol Chem282: 18945–18952.

Lobley A et al. (2003). Reprod Biol Endocrinol1: 53.

Navarro B et al. (2007). Proc Natl Acad Sci USA104: 7688–7692.

Qi H et al. (2007). Proc Natl Acad Sci USA104: 1219–1223.

Quill TA et al. (2001). Proc Natl Acad Sci USA98: 12527–12531.

Ren D et al. (2001). Nature413: 603–609.

Citation Information

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

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

Chloride

Overview: Chloride channels are a functionally and structurally diverse group of anion selective channels involved in processes including the regulation of the excitability of neurones, skeletal, cardiac and smooth muscle, cell volume regulation, transepithelial salt transport, the acidification of internal and extracellular compartments, the cell cycle and apoptosis (reviewed by Nilius and Droogmans, 2003). Excluding the transmitter-gated GABA and glycine receptors (see separate tables), well characterised chloride channels can be classified as the voltage-sensitive ClC subfamily, calcium-activated channels, high (maxi) conductance channels, the cystic fibrosis transmembrane conductance regulator (CFTR) and volume regulated channels. No official recommendation exists regarding the classification of chloride channels. Functional chloride channels that have been cloned from, or characterised within, mammalian tissues are listed.

ClC-family: The mammalian ClC family (reviewed by Jentsch et al., 2002; Nilius and Droogmans, 2003; Chen, 2005; Jentsch et al., 2005a, b; Dutzler, 2006) contains 9 members that fall into three groups; ClC-1, ClC-2, hClC-Ka (rClC-K1) and hClC-Kb (rClC-K2); ClC-3 to ClC-5, and ClC-6 and −7. ClC-1 and ClC-2 are plasma membrane chloride channels as are ClC-Ka and ClC-Kb (largely expressed in the kidney) when associated with barttin (ENSG00000162399), a 320 amino acid 2TM protein (Estévez et al., 2001). The localisation of CIC-3 (ENSG00000109572), ClC-4 (ENSG00000073464) and ClC-5 (ENSG00000171365) is likely to be predominantly intracellular and recent reports indicate that ClC-4 and ClC-5 (and by inference ClC-3) function as Cl/H+ antiporters, rather than classical Cl channels (Picollo and Pusch, 2005; Scheel et al., 2005; reviewed by Miller, 2006 & Pusch et al., 2006). An intracellular location has been demonstrated for ClC-6 (ENSG00000011021) and ClC-7 (ENSG00000103249) also (reviewed by Jentsch et al., 2005b). Alternative splicing increases the structural diversity within the ClC family (e.g. for ClC-2, ClC-3 ClC-5 and ClC-6). The crystal structure of two bacterial ClC channels has been described (Dutzler et al., 2002). Each ClC subunit, with a complex topology of 17 intramembrane α-helices, contributes a single pore to a dimeric ‘double-barrelled’ ClC channel that contains two independently-gated pores, confirming the predictions of previous functional and structural investigations (reviewed by Estévez and Jentsch, 2002; Babini and Pusch, 2004; Chen, 2005; Dutzler, 2006). As found for ClC-4 and ClC-5, the prokaryotic ClC homologue functions as an H+ /Cl antiporter, rather than as an ion channel (Accardi and Miller, 2004).

NomenclatureClC-1ClC-2ClC-KaClC-Kb
Other namesSkeletal muscle Cl channelClC-K1 (rodent)ClC-K2 (rodent)
Ensembl IDENSG00000186544ENSG00000114859ENSG00000186510ENSG00000184908
ActivatorsConstitutively activeArachidonic acid, amidation, acid-activated omeprazole, lubiprostone (SPI-0211)Constitutively active (when co-expressed with barttin)Constitutively active (when co-expressed with barttin)
BlockersS-(—)CPP, S-(—)CPB, 9-AC, Cd2+, Zn2+, niflumic acidDPC, Cd2+, Zn2+3-phenyl-CPP, DIDS3-phenyl-CPP, DIDS
Functional characteristicsγ = 1-1.5 pS; voltage-activated (depolarization); inwardly rectifying; deactivation upon repolarization (by fast gating of single protopores and a slower common gate), inhibited by ATP binding to cytoplasmic cystathionine β-synthetase related (CBS) domains, inhibited by intracellular acidosis in the presence of ATPγ = 2-3 pS; voltage-activated (hyperpolarization), inward rectification (steady state currents); slow inactivation (seconds); activated by cell swelling, PKA and weak extracellular acidosis; inhibited by phosphorylation by p34(cdc2)/cyclin B; cell surface expression and activity increased by association with Hsp90Slight outward rectification; largely time-independent currents; inhibited by extracellular acidosis; potentiated by extracellular Ca2+ and niflumic acid (10-1000 μM)Slight outward rectification; largely time-independent currents; inhibited by extracellular acidosis; potentiated by extracellular Ca2+ and niflumic acid (10-1000 μM)
NomenclatureClC-3ClC-4ClC-5
Ensembl IDENSG00000109572ENSG00000073464ENSG00000171365
ActivatorsHigh constitutive activity (disputed)
BlockersDIDS (disputed), tamoxifen, (not DPC or A-9-C)
Functional characteristicsγ = 40 pS (at depolarised potentials); outward rectification; activity enhanced by cell swelling (disputed) and by CaM kinase II; inhibited by PKC activation (disputed); inactivates at positive potentialsCl/H+ antiporter (Picollo and Pusch, 2005; Scheel et al., 2005); extreme outward rectification; largely time-independent currents; inhibited by extracellular acidosis; ATP hydrolysis required for full activityCl/H+ antiporter (Picollo and Pusch, 2005; Scheel et al., 2005); extreme outward rectification; largely time-independent currents; inhibited by extracellular acidosis

ClC channels other than ClC-3 display the permeability sequence Cl > Br > I (at physiological pH); for ClC-3, I > Cl. ClC-1 has significant opening probability at resting membrane potential, accounting for 75% of the membrane conductance at rest in skeletal muscle, and is important for repolarization and for stabilization of the membrane potential. S-(—)CPP, A-9-C and niflumic acid act intracellularly and exhibit a strongly voltage-dependent block with strong inhibition at negative voltages and relief of block at depolarized potentials (Liantonio et al., 2007 and reviewed by Pusch et al., 2002). Mutations in the ClC-1 gene result in myotonia congenita. Although ClC-2 can be activated by cell swelling, it does not correspond to the VRAC channel (see below). Alternative potential physiological functions for ClC-2 are reviewed by Jentsch et al. (2005b). Disruption of the ClC-2 gene in mice is associated with testicular and retinal degeneration. Functional expression of human ClC-Ka and ClC-Kb requires the presence of barttin (Estévez et al., 2001; Scholl et al., 2006). The rodent homologue (ClC-K1) of ClC-Ka demonstrates limited expression as a homomer, but its function is enhanced by barttin which increases both channel opening probablility in the physiological range of potentials and single channel conductance (Estévez et al., 2001; Scholl et al., 2006). Knock out of the ClC-K1 channel induces nephrogenic diabetes insipidus. Classic (type III) Bartter's syndrome and Gitelman's variant of Bartter's syndrome are associated with mutations of the ClC-Kb chloride channel (reviewed by Jentsch et al., 2005b; Uchida and Sasaki, 2005). ClC-Ka is approximately 5 to 6-fold more sensitive to block by 3-phenyl-CPP and DIDS than ClC-Kb (Liantonio et al., 2002). The biophysical and pharmacological properties of ClC-3, and the relationship of the protein to the endogenous volume-regulated anion channel(s) VRAC (see Guan et al., 2006 and below) are controversial and further complicated by the inference that ClC-3 is a Cl/H+ exchanger, rather than an ion channel (Picollo and Pusch, 2005). Activation of heterologously expressed ClC-3 by cell swelling in response to hypotonic solutions is disputed, as are other aspects of regulation, including inhibition by PKC. Lack of chloride ion channel function of ClC-3 heterologously expressed in HEK 293 cells, and inserted in to the plasma membrane, has additionally been claimed. However, phosphorylation by exogenously introduced CaM kinase II may be required for high activity of ClC-3 in this paradigm. In ClC-3 knock-out mice (Clcn3−/-), volume regulated anion currents (ICl,swell) persist (Stobrawa et al., 2001; Arreola et al., 2002), and demonstrate kinetic, ionic selectivity and pharmacological properties similar to ICl,swell recorded from cells of wild-type (Clcn3+/+) animals, indicating that ClC-3 is not indispensable for such regulation (Yamamoto-Mizuma et al., 2004). However, both ClC-3 antisense and novel anti-ClC-3 antibodies are reported to reduce VRAC function in several cell systems (e.g. Hermoso et al., 2002; Wang et al., 2003), and the sensitivity of ICl,swell to regulators such as PKC, [ATP]i and [Mg2+]i differs between cells of Clcn3(+/+) and Clcn3(-/-) mice (Yamamoto-Mizuma et al., 2004). A splice variant of ClC-3 (i.e. ClC-3B) upregulated by NHERF, is expressed in the plasma membrane of epithelial cells and mediates outwardly rectifying currents activated by depolarisation. In association with CFTR, ClC-3B is activated by PKA. ClC-3B is a candidate for the outwardly rectifying chloride channel ORCC (Ogura et al., 2002). Results obtained from ClC-3 knock-out mice suggest an endosomal/synaptic vesicle location for the channel and a role, via the dissipation of electrical potential, in the acidification of vesicles. Mice lacking ClC-3 display total degeneration of the hippocampus and retinal degeneration (Stobrawa et al., 2001; Jentsch et al., 2005b). Loss-of-function mutations of ClC-5 are associated with proteinuria, hypercalciuria and kidney stone formation (Dent's disease). A ClC 5 knock-out provides a mouse model of this disease. Disruption of the ClC-7 gene in mice leads to osteopetrosis, blindness and lysosomal dysfunction (Jentsch et al., 2005b).

CFTR: CFTR, a 12TM, ABC type protein, is a cAMP-regulated epithelial cell membrane Cl channel involved in normal fluid transport across various epithelia. The most common mutation in CFTR (i.e. the deletion mutant, Δ508) results in impaired trafficking of CFTR and reduces its incorporation into the plasma membrane causing cystic fibrosis. In addition to acting as an anion channel per se, CFTR may act as a regulator of several other conductances including inhibition of the epithelial Na channel (ENaC), calcium activated chloride channels (CaCC) and volume regulated anion channel (VRAC), activation of the outwardly rectifying chloride channel (ORCC), and enhancement of the sulphonylurea sensitivity of the renal outer medullary potassium channel (ROMK2), (reviewed by Nilius and Droogmans, 2003). CFTR also regulates TRPV4, which provides the Ca2+ signal for regulatory volume decrease in airway epithelia (Arniges et al., 2004). The activities of CFTR and the chloride-bicarbonate exchangers SLC26A3 (DRA) and SLC26A6 (PAT1) are mutually enhanced by a physical association between the regulatory (R) domain of CFTR and the STAS domain of the SCL26 transporters, an effect facilitated by PKA-mediated phosphorylation of the R domain of CFTR (Ko et al., 2004).

NomenclatureCFTR
Other namesABCC7
Ensembl IDENSG00000001626
ActivatorsFlavones (e.g. UCCF-339, UCCF-029, apigenin, genistein), benzimidazolones (e.g. UCCF-853, NS004), benzoquinolines (e.g. CBIQ), psoralens (8-methoxypsoralen), 1,4-dihydropyridines (e.g. felopidine, nimodipine), capsaicin, phenylglycines (e.g. 2-[(2-1H-indol-3-yl-acetyl)-methylamino]-N-(4-isopropylphenyl)-2-phenylacetamide), sulfonamides (e.g. 6-(ethylphenylsulfamoyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid cycloheptylamide)
BlockersGlyH-101, CFTRinh-172, glibenclamide
Functional characteristicsγ = 6-10 pS; permeability sequence = Brgeqslant R: gt-or-equal, slantedCl>Igeqslant R: gt-or-equal, slantedF, (PI/PCl = 0.1-0.85); slight outward rectification; phosphorylation necessary for activation by ATP binding at binding nucleotide binding domains (NBD)1 and 2; positively regulated by PKC and PKGII (tissue specific); regulated by several interacting proteins including syntaxin 1A, Munc18 and PDZ domain proteins such as NHERF (EBP50) and CAP70

CFTR contains two cytoplasmic nucleotide binding domains (NBDs) that bind ATP. A single open-closing cycle is hypothesised to involve, in sequence: binding of ATP at the N-terminal NBD1, ATP binding to the C-terminal NBD2 leading to the formation of an intramolecular NBD1-NBD2 dimer associated with the open state, and subsequent ATP hydrolysis at NBD2 facilitating dissociation of the dimer and channel closing, and the initiation of a new gating cycle (Vergani et al., 2005; Aleksandrov et al., 2007). Phosphorylation by PKA at sites within a cytoplasmic regulatory (R) domain are required for the binding ATP to gate CFTR (Gadsby et al., 2006). PKC (and PKGII within intestinal epithelial cells via guanylin-stimulated cGMP formation) positively regulate CFTR activity.

Calcium activated chloride channel: Chloride channels activated by intracellular calcium (CaCC) are widely expressed in excitable and non-excitable cells where they perform diverse functions (Hartzell et al., 2005). The molecular nature of CaCC is unclear. Members of the initial putative calcium-activated chloride channel proteins (the CLCA family) have been cloned from human, murine, bovine and porcine species (reviewed by Loewen and Forsyth, 2005), but their similarity to endogenous CaCC is slim (e.g. Britton et al., 2002; Eggermont, 2004) and doubt has been cast on their existence as ion channels (e.g. Gibson et al., 2005). CLCAs now appear to function as cell adhesion proteins, or are secreted proteins but the properties of CLCA isoforms may be modified by auxillary subunits (Greenwood et al., 2002). More recently the Best gene family (hbest1-4) have been identified whose expression products (bestrophins) have a topology more consistent with ion channels (see Hartzell et al., 2005). Moreover, mutation of amino acids in the theoretical pore region affects anion conductance and the channels are activated by physiological concentrations of intracellular Ca2+ in a heterologous expression system (Qu et al., 2003, 2004).

NomenclatureCaCC
Other namesCa2+-activated Cl channel
ActivatorsIntracellular Ca2+
BlockersNiflumic acid, flufenamic acid, DCDPC, DIDS, SITS, NPPB, A-9-C, Ins(3,4,5,6)P4, mibefradil, fluoxetine
Functional characteristicsγ = 0.5-5 pS; permeability sequence, SCN > NO3 > I > Br > Cl > F; relative permeability of SCN:Cl∼8. I:Cl∼3, aspartate:Cl∼0.15, outward rectification (decreased by increasing [Ca2+]i); sensitivity to activation by [Ca2+]i decreased at hyperpolarized potentials; slow activation at positive potentials (accelerated by increasing [Ca2+]i); rapid deactivation at negative potentials, deactivation kinetics modulated by anions binding to an external site; modulated by redox status

Blockade of ICl(Ca) by niflumic acid, DIDS and 9-AC is voltage-dependent whereas block by NPPB is voltage-independent (Hartzell et al., 2005). Extracellular niflumic acid; DCDPC and A-9-C (but not DIDS) exert a complex effect upon ICl(Ca) in vascular smooth muscle, enhancing and inhibiting inwardly and outwardly directed currents in a manner dependent upon [Ca2+]i (see Leblanc et al., 2005 for summary). Considerable crossover in pharmacology with large conductance Ca2+-activated K+ channels also exists (see Greenwood and Leblanc, 2007 for overview). CaMKII modulates CaCC in a tissue dependent manner (reviewed by Hartzell et al., 2005; Leblanc et al., 2005). CaMKII inhibitors block activation of ICl(Ca) in T84 cells but have no effect in parotid acinar cells. In tracheal and arterial smooth muscle cells, but not portal vein myocytes, inhibition of CaMKII reduces inactivation of ICl(Ca). Intracellular Ins(3,4,5,6)P4 may act as an endogenous negative regulator of CaCC channels activated by Ca2+, or CaMKII. Smooth muscle CaCC are also regulated positively by Ca2+-dependent phosphatase, calcineurin (see Leblanc et al., 2005 for summary).

Maxi chloride channel: Maxi Cl channels are high conductance, anion selective, channels initially characterised in skeletal muscle and subsequently found in many cell types including neurones, glia, cardiac muscle, lymphocytes, secreting and absorbing epithelia, macula densa cells of the kidney and human placenta syncytiotrophoblasts. The physiological significance of the maxi Cl channel is uncertain, but roles in cell volume regulation and apoptosis have been claimed. Evidence suggests a role for maxi Cl channels as a conductive pathway in the swelling-induced release of ATP from mouse mammary C127i cells that may be important for autocrine and paracrine signalling by purines (Sabirov et al., 2001; Dutta et al., 2002). A similar channel mediates ATP release from macula densa cells within the thick ascending of the loop of Henle in response to changes in luminal NaCl concentration (Bell et al., 2003). A family of human high conductance Cl channels (TTYH1-3) that resemble Maxi Cl channels has been cloned (Suzuki and Mizuno, 2004), but alternatively, Maxi Cl channels have also been suggested to correspond to the voltage-dependent anion channel, VDAC, expressed at the plasma membrane (Bahamonde et al., 2003; Okada et al., 2004).

NomenclatureMaxi Cl
Other namesHigh conductance anion channel, volume- and voltage-dependent ATP-conductive large conductance (VDACL) anion channel
ActivatorsG-protein-coupled receptors, cytosolic GTPγS, extracellular triphenylethylene anti-oestrogens (tamoxifen, toremifine), extracellular chlorpromazine and triflupromazine, cell swelling
BlockersSITS, DIDS, NPPB, DPC, intracellular arachidonic acid, extracellular Zn2+ and Gd3+
Functional characteristicsγ = 280–430 pS (main state); permeability sequence, I>Br>Cl>F>gluconate (PClPCl = ∼1.5); ATP is a voltage dependent permeant blocker of single channel activity (PATP/PCl = 0.08–0.1); channel activity increased by patch-excision; channel opening probability (at steady-state) maximal within approximately ± 20 mV of 0 mV, opening probability decreased at more negative and (commonly) positive potentials yielding a bell-shaped curve; channel conductance and opening probability regulated by annexin 6

Differing ionic conditions may contribute to variable estimates of γ reported in the literature (Km = 120 mM in symmetrical Cl). Inhibition by arachinonic acid (and cis-unsaturated fatty acids) is voltage-independent, occurs at an intracellular site, and involves both channel shut down (Kd = 4–5 μM) and a reduction of γ (Kd = 13–14 μM). Blockade of channel activity by SITS, DIDS, Gd3+ and arachidonic acid is paralleled by decreased swelling-induced release of ATP (Sabirov et al., 2001; Dutta et al., 2002). Channel activation by anti-oestrogens in whole cell recordings requires the presence of intracellular nucleotides and is prevented by pre-treatment with 17β-oestradiol, dibutryl cAMP, or intracellular dialysis with GDPγS (Diaz et al., 2001). Activation by tamoxifen is suppressed by low concentrations of okadaic acid, suggesting that a dephosphorylation event by protein phosphatase PP2A occurs in the activation pathway (Diaz et al., 2001). In contrast, 17β-estradiol and tamoxifen appear to directly inhibit the maxi Cl channel of human placenta reconstituted into giant liposomes and recorded in excised patches (Riquelme, 2006).

Volume regulated chloride channels: Volume activated chloride channels (also termed VSOAC, volume-sensitive organic osmolyte/anion channel; VRC, volume regulated channel and VSOR, volume expansion-sensing outwardly rectifying anion channel) participate in regulatory volume decrease (RVD) in response to cell swelling. VRAC may also be important for several other processes including the regulation of membrane excitability, transcellular Cl transport, angiogenesis, cell proliferation and apoptosis (reviewed by Nilius and Droogmans, 2003; Okada et al., 2004, Mulligan and MacVicar, 2006). VRAC may not be a single entity, but may instead represent a number of different channels that are expressed to a variable extent in different tissues and are differentially activated by cell swelling. See the discussion above for the role of CLC-3 in VRAC. In addition to CLC-3 expression products several former VRAC candidates including MDR1 P-glycoprotein, Icln, Band 3 anion exchanger and phospholemman are also no longer considered likely to fulfil this function (see reviews by Jentsch et al., 2002; d'Angelmont de Tassigny et al., 2003; Nilius and Droogmans, 2003; Sardini et al., 2003, Okada, 2006).

NomenclatureVRAC (volume regulated anion channel), VSOAC (volume-sensitive organic osmolyte/anion channel), VRC (volume regulated channel), VSOR (volume expansion-sensing outwardly rectifying anion channel)
ActivatorsCell swelling; low intracellular ionic strength; GTPγS
BlockersNS3728, DCPIB, clomiphene, nafoxidine, mefloquine, tamoxifen, gossypol, arachidonic acid, mibefradil, NPPB, quinine, quinidine, chromones NDGA, A-9-C, DIDS, 1,9-dideoxyforskolin, oxalon dye (diBA-(5)-C4), extracellular nucleotides, nucleoside analogues, intracellular Mg2+
Functional characteristicsγ = 10–20 pS (negative potentials), 50–90 pS (positive potentials); permeability sequence SCN > I > NO3 > Br > Cl > F > gluconate; outward rectification due to voltage dependence of γ; inactivates at positive potentials in many, but not all, cell types; time dependent inactivation at positive potentials; intracellular ionic strength modulates sensitivity to cell swelling and rate of channel activation; rate of swelling-induced activation is modulated by intracellular ATP concentration; ATP dependence is independent of hydrolysis and modulated by rate of cell swelling; inhibited by increased intracellular free Mg2+ concentration; tyrosine phosphorylation step(s) may modulate channel activation; swelling induced activation of VRAC requires a functional Rho-Rho kinase MLCK phosphorylation pathway, but not activation of the pathway (i.e. a permissive effect); regulation by PKCα required for optimal activity; cholesterol depletion enhances activity; activated by direct stretch of β1-integrin

In addition to conducting monovalent anions, in many cell types the activation of VRAC by a hypotonic stimulus can allow the efflux of organic osmolytes such as amino acids and polyols that may contribute to RVD.

Other chloride channels: In addition to intracellular chloride channels that are not considered here, plasma membrane channels other than those listed have been functionally described. Many cells and tissues contain outwardly rectifying chloride channels (ORCC) that may correspond to VRAC active under isotonic conditions and, as noted above, possibly ClC-3B (Ogura et al., 2002). A cAMP-activated Cl channel that does not correspond to CFTR has been described in intestinal Paneth cells (Tsumura et al., 1998). A Cl channel activated by cGMP with a dependence on raised intracellular Ca2+ has been recorded in various vascular smooth muscle cells types, which has a pharmacology very different from the ‘conventional’ CaCC (see Matchkov et al., 2004; Piper and Large, 2004). A proton-activated, outwardly rectifying anion channel has also recently been described (Lambert and Oberwinkler, 2005).

Abbreviations: A-9-C, anthracene-9-carboxylic acid; CBIQ, 4-chlorobenzo[F]isoquinoline; CFTRinh-172, 3-[(3-trifluoromethyl)phenyl]-5-[(4-carboxyphenyl)methylene]-2-thioxo-4-thiazolidinone; DCPIB, 4-(2-butyl-6,7-dichlor-2-cyclopentyl-indan-1-on-5-yl) oxybutyric acid; diBA-(5)-C4, bis-(1,3-dibutylbarbituric acid)pentamethine oxanol; DIDS, 4,4′-diisothiocyanostilbene-2,2′-disulphonic acid; DNDS, 4,4′-dinitrostilbene-2,2′-disulphonic acid; DPC, diphenylamine carboxylic acid; DPDPC, dichloro-diphenylamine 2-carboxylic acid; GlyH-101, N-(2-naphthalenyl)-[(3,5-dibromo-2,4-dihydroxyphenyl)methylene]glycine hydrazide; NDGA, nordihydroguiaretic acid; NPA, N-phenylanthracilic acid; NPPB, 5-nitro-2-(3-phenylpropylamino)benzoic acid; NS004, 5-trifluoromethyl-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-2H-benzimidazole-2-one; NS3728, N-[3,5-bis(trifluromethyl)-phenyl]-N'[4-bromo-2-(1H-tetrazol-5yl)-phenyl]urea; S-(-)CPB, S-(-)2-(4-chlorophenoxy)butyric acid; S-(-)CPP, S-(-)2-(4-chlorophenoxy)propionic acid; SITS, 4′-isothiocyanostilbene-2,2′-disulphonic acid; UCCF-029, 2-(4-pyridinium)benzo[h]4H-chromen-4-one bisulfate; UCCF-180, 3-(3-butynyl)-5-methoxy-1-phenylpyrazole-4-carbaldehyde; UCCF-853, 1-(3-chlorophenyl)-5-trifluoromethyl-3-hydroxybenzimidazol-2-one

Further Reading

Aleksandrov AA, Aleksandrov LA, Riordan JR (2007). CFTR (ABCC7) is a hydrolyzable-ligand-gated channel. Pflugers Arch453: 693–702.

Aromataris EC, Rychkov GY (2006). ClC-1 chloride channel: matching its properties to a role in skeletal muscle. Clin Exp Pharmacol Physiol33: 1118–1123.

Babini E, Pusch MA (2004). Two-holed story: structural secrets about ClC proteins become unraveled? Physiology (Bethesda)19: 293–299.

Chen T-Y (2005). Structure and function of CLC channels. Annu Rev Physiol67: 809–839.

D'Anglemont DE, Tassingny A, Souktane R, Ghaleh B, Henry P, Berdeaux A (2003). Structure and pharmacology of swelling-sensitive chloride channels, ICl, swell., Fundam Clin Pharmacol17: 539–553.

Dutzler R (2006). The ClC family of chloride channels and transporters. Curr Opin Struct Biol16: 439–446.

Dutzler R (2007). A structural perspective on ClC channel and transporter function. FEBS Lett581: 2839–2844.

Eggermont J (2004). Calcium activated chloride channels: (Un)known, (Un)loved? Proc Am Thorac Soc1: 22–27.

Eggermont J, Trouet D, Carton I, Nilius B (2001). Cellular function and control of volume regulated anion channels. Cell Biochem Biophys35: 263–274.

Estévez R, Jentsch TJ (2002). CLC chloride channels: correlating structure with function. Curr Opin Struct Biol12: 531–539.

Fahlke C (2001). Ion permeation and selectivity in ClC-type chloride channels. Am J Physiol280: F748–F757.

Gadsby DC, Vergaini P, Csanady L (2006). The ABC protein turned chloride channel whose failure causes cystic fibrosis. Nature440: 477–483.

Greenwood IA, Leblanc N (2007). Overlapping pharmacology of Ca2+-activated Cl and K+ channels. Trends Pharmacol Sci28: 1–5.

Guan Y-Y, Wang G-L, Zhou J-G (2006). The ClC-3 Cl-channel in cell volume regulation, proliferation and apoptosis in vascular smooth muscle cells. Trends Pharmacol Sci27: 290–296.

Hartzell C, Putzier I, Arreola J (2005). Calcium-activated chloride channels. Annu Rev Physiol67: 719–758.

Jentsch TJ, Neagoe I, Scheel O (2005a). CLC channels and transporters. Curr Opin Neurobiol15: 319–325.

Jentsch TJ, Poet M, Fuhrmann JC, Zdebik AA (2005b). Physiological functions of CLC Cl- channels gleaned from human genetic disease and mouse models. Annu Rev Physiol67: 779–807.

Jentsch TJ, Stein V, Weinreich F, Zdebik AA (2002). Molecular structure and physiological function of chloride channels. Physiol Rev82: 503–568.

Leblanc N, Ledoux J, Saleh S, Sanguinetti A, Angermann J, O'Driscoll K et al. (2005). Regulation of calcium-activated chloride channels in smooth muscle cells: a complex picture is emerging. Can J Physiol Pharmacol83: 541–556.

Loewen ME, Forsyth GW (2005). Structure and function of CLCA proteins. Physiol Rev85: 1061–1092.

Miller C (2006). ClC chloride channels viewed through a transporter lens. Nature440: 484–489.

Mulligan SJ, MacVicar BA (2006). VRACs CARVe a path for novel mechanisms of communication in the CNS. Sci STKE357: pe42.

Nilius B, Droogmans G (2003). Amazing chloride channels: an overview. Acta Physiol Scand177: 119–147.

Nilius B, Eggermont J, Droogmans G (2000). The endothelial volume-regulated anion channel, VRAC. Cell Physiol Biochem10: 313–320.

Okada Y, Maeno E, Shimizu T, Manabe K, Mori S, Nabekura T (2004). Dual roles of plasmalemmal chloride channels in induction of cell death. Pflügers Arch448: 287–295.

Okada Y (2006). Cell-volume sensitive chloride channels: phenotypic properties and molecular identity. Contrib Nephrol152: 9–24.

Puljak L, Kilic G (2006). Emerging roles of chloride channels in human diseases. Biochim Biopsy Acta1762: 404–413.

Pusch M (2004). Structural insights into chloride and proton-mediated gating of CLC chloride channels. Biochemistry43: 1135–1144.

Pusch M, Accardi A, Liantonio A, Guida P, Traverso S, Camerino DC et al. (2002). Mechanisms of block of muscle type CLC chloride channels. Mol Membr Biol19: 285–292.

Pusch M, Zifarelli G, Murgia AR, Picollo A, Babini E (2006). Channel or transporter? The CLC saga continues. Exp Physiol91: 149–152.

Riordan JR (2005). Assembly of functional CFTR chloride channels. Annu Rev Physiol67: 701–718.

Riquelme G (2006). Apical maxi-chloride channel from the human placenta: 12 years after the first electrophysiological recordings. Biol Res39: 437–445.

Sardini A, Amey JS, Weylandt KH, Nobles M, Valverde MA, Higgins CF (2003). Cell volume regulation and swelling-activated chloride channels. Biochim Biophys Acta1618: 153–162.

Suzuki M, Mizuno A (2004). A novel human Cl(-) channel family related to Drosophila flightless locus. J Biol Chem279: 22461–22468.

Thiagarajah JR, Verkman AS (2003). CFTR pharmacology and its role in intestinal fluid secretion. Curr Opin Pharmacol3: 594–599.

Uchida S, Sasaki S (2005). Function of chloride channels in the kidney. Annu Rev Physiol67: 759–778.

Verkman AS, Lukacs GL, Galietta LJ (2006). CFTR chloride channel drug discovery-inhibitors as antidiarrheals and activators for therapy of cystic fibrosis. Curr Pharm Des12: 2235–2247.

Zifarelli G, Pusch M (2007). CLC chloride channels and transporters: a biophysical and physiological perspective. Rev Physiol Biochem Pharmacol158: 23–76.

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Liantonio A et al. (2002). Mol Pharmacol62: 265–271.

Liantonio A et al. (2007). Br J Pharmacol150: 235–247.

Matchkov VV et al. (2004). J Gen Physiol123: 121–134.

Ogura T et al. (2002). FASEB J16: 863–865.

Okada SF et al. (2004). J Gen Physiol124: 513–526.

Picollo A, Pusch M (2005). Nature436: 420–423.

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Stobrawa SM et al. (2001). Neuron29: 185–196.

Suzuki M, Mizuno A (2004). J Biol Chem279: 22461–22468.

Tsumura T et al. (1998). J Physiol512: 765–777.

Vergani P et al. (2005). Biochem Soc Trans33: 1003–1007.

Wang GX et al. (2003). Am J Physiol Heart Circ Physiol285: H1453–H1463.

Yamamoto-Mizuma S et al. (2004). J Physiol557: 439–356.

Citation Information

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

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

Connexins and pannexins

Overview: Gap junctions are essential for many physiological processes including cardiac and smooth muscle contraction, regulation of neuronal excitability and epithelial electrolyte transport (see Evans and Martin, 2002; Bruzzone et al., 2003; Connors and Long, 2004). Gap junction channels allow the passive diffusion of molecules of up to 1000 Daltons which can include nutrients, metabolites and second messengers (such as IP3) as well as cations and anions. 21 connexin genes (Cx23, Cx25, Cx26, Cx30, Cx30.2, Cx30.3, Cx31, Cx31.1, Cx31.9, Cx32, Cx36, Cx37, Cx40, Cx40.1, Cx43, Cx45, Cx46, Cx47, Cx50, Cx59, Cx62) and 3 pannexin genes (Px1, Px2, Px3; which are structurally related to the invertebrate innexin genes) code for gap junction proteins in humans. Each connexin gap junction comprises 2 hemichannels or ‘connexons’ which are themselves formed from 6 connexin molecules. The various connexins have been observed to combine into both homomeric and heteromeric combinations, each of which may exhibit different functional properties. It is also suggested that individual hemichannels formed by a number of different connexins might be functional in at least some cells (see Herve et al., 2007). Connexins have a common topology, with four α-helical transmembrane domains, two extracellular loops, a cytoplasmic loop, and N- and C-termini located on the cytoplasmic membrane face. In mice, the most abundant connexins in electrical synapses in the brain seem to be Cx36, Cx45 and Cx57 (Sohl et al., 2005). Mutations in connexin genes are associated with the occurrence of a number of pathologies, such as peripheral neuropathies, cardiovascular diseases and hereditary deafness. The pannexin genes Px1 and Px2 are widely expressed in the mammalian brain (Vogt et al., 2005). Like the connexins, at least some of the pannexins can form functional hemichannels (Bruzzone et al., 2003; Pelegrin and Surprenant, 2007).

 ConnexinsPannexins
NomenclatureCx23, Cx25, Cx26, Cx30, Cx30.2, Cx30.3, Cx31, Cx31.1, Cx31.9, Cx32, Cx36, Cx37, Cx40, Cx40.1, Cx43, Cx45, Cx46, Cx47, Cx50, Cx59, Cx62Px1, Px2, Px3
Ensembl IDENSG00000159248 (Cx36)aENSG00000110218 (Px1) ENSG00000073150 (Px2) ENSG00000154143 (Px3)
InhibitorsCarbenoxoloneCarbenoxolone
 Flufenamic acid Octanol Raising external calciumLittle block by flufenamic acid Unaffected by raising external calcium

Connexins are most commonly named according to their molecular weights, so, for example, Cx23 is the connexin protein of 23 kDa. This can cause confusion when comparing between species - for example the mouse connexin Cx57 is orthologous to the human connexin Cx62. No natural toxin or specific inhibitor of junctional channels has been identified yet however two compounds often used experimentally to block connexins are carbenoxolone and flufenamic acid (Salamah and Dhein, 2005). At least some pannexin hemichannels are more sensitive to carbenoxolone than connexins but much less sensitive to flufenamic acid (Bruzzone et al., 2005). Recently it has been suggested that 2-aminoethoxydiphenyl borate (2-APB) may be a more effective blocker of some connexin channel subtypes (Cx26, Cx30, Cx36, Cx40, Cx45, Cx50) compared to others (Cx32, Cx43, Cx46, Bai et al., 2006).

aDue to space constraints, the Ensembl ID for only connexin Cx36 is given. Ensembl information for the other connexins can be found from links therein.

Further Reading

Bennett MV, Zukin RS (2004). Electrical coupling and neuronal synchronization in the mammalian brain. Neuron41: 495–511.

Connors BW, Long MA (2004). Electrical synapses in the mammalian brain. Annu Rev Neurosci27: 393–418.

Cruciani V, Mikalsen SO (2006). The vertebrate connexin family. Cell Mol Life Sci63: 1125–1140.

Evans WH, De Vuyst E, Leybaert L (2006). The gap junction cellular internet: connexin hemichannels enter the signalling limelight. Biochem J397: 1–14.

Evans WH, Martin PEM (2002). Gap junctions: structure and function. Mol Memb Biol19: 121–136.

Harris AL (2007). Connexin channel permeability to cytoplasmic molecules. Prog Biophys & Mol Biol94: 120–143.

Herve JC (2007). Gap junction channels: from protein genes to diseases. Prog Biophys & Mol Biol94: 1–4.

Herve JC, Bourmeyster N, Sarrouilhe D, Duffy HS (2007). Gap junctional complexes: from partners to functions. Prog Biophys & Mol Biol94: 29–65.

Herve JC, Phelan P, Bruzzone R, White TW (2005). Connexins, innexins and pannexins: Bridging the communication gap. Biochem Biophys Acta1719: 3–5.

Herve JC, Sarrouilhe D (2005). Connexin-made channels as pharmacological targets. Curr Pharm Des11: 1941–1958.

Homuzdi SG, Filippov MA, Mitropoulou G, Monyer H, Bruzzone R (2004). Electrical synapses: a dynamic signaling system that shapes the activity of neuronal networks. Biochem Biophys Acta1662: 113–137.

Kumar NM, Gilula NB (1996). The gap junction communication channel. Cell84: 381–388.

Salameh A, Dhein S (2005). Pharmacology of gap junctions: New pharmacological targets for treatment of arrhythmia, seizure and cancer? Biochem Biophys Acta1719: 36–58.

Sohl G, Maxeiner S, Willecke K (2005). Expression and functions of neuronal gap junctions. Nature Rev Neurosci6: 191–200.

Spray DC, Dermietzel R (1996). Neuroscience Intelligence Unit: Gap Junctions in the Nervous System. Springer: New York.

Yen MR, Saier MH (2007). Gap junctional proteins of animals: The innexin/pannexin superfamily. Prog Biophys Mol Biol94: 5–14.

References

Bai D et al. (2006). J Pharmacol Exp Ther319: 1452–1458.

Bruzzone R et al. (2003). Proc Natl Acad Sci USA100: 13644–13649.

Bruzzone R et al. (2005). J Neurochem92: 1033–1043.

Pelegrin P, Surprenant A (2007). J Biol Chem282: 2386–2394.

Vogt A et al. (2005). Brain Res Mol Brain Res141: 113–120.

Citation Information

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

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

Cyclic nucleotide-gated

Overview: Cyclic nucleotide-gated (CNG) channels are responsible for signalling in the primary sensory cells of the vertebrate visual and olfactory systems. A standardised nomenclature for CNG channels has been proposed by the NC-IUPHAR subcommittee on voltage-gated ion channels (see Hofmann et al., 2005).

CNG channels are voltage-independent cation channels formed as tetramers. Each subunit has 6TM, with the pore-forming domain between TM5 and TM6. CNG channels were first found in rod photoreceptors (Fesenko et al., 1985; Kaupp et al., 1989), where light signals through rhodopsin and transducin to stimulate phosphodiesterase and reduce intracellular cGMP level. This results in a closure of CNG channels and a reduced ‘dark current’. Similar channels were found in the cilia of olfactory neurons (Nakamura and Gold, 1987) and the pineal gland (Dryer and Henderson, 1991). The cyclic nucleotides bind to a domain in the C terminus of the subunit protein: other channels directly binding cyclic nucleotides include HCN, eag and certain plant potassium channels.

NomenclatureCNGA1CNGA2CNGA3
Other namesCNG1, CNGα1, RCNC1CNG2, CNGα3, OCNC1CNG3, CNGα2, CCNC1
Ensembl IDENSG00000198515ENSG00000183862ENSG00000144191
ActivatorsIntracellular cyclic nucleotides: cGMP (EC50∼30 μM)>> cAMPIntracellular cyclic nucleotides: cGMP∼cAMP (EC50∼1 μM)Intracellular cyclic nucleotides: cGMP (EC50∼30 μM)>> cAMP
InhibitorsL-cis diltiazemL-cis diltiazem
Functional characteristicsγ=25-30 pSγ=35 pSγ=40 pS
 PCa/PNa = 3.1PCa/PNa = 6.8PCa/PNa = 10.9

CNGA1, CNGA2 and CNGA3 express functional channels as homomers. Three additional subunits CNGA4 (Genbank protein AAH40277), CNGB1 (Q14028) and CNGB3 (NP_061971) do not, and are referred to as auxiliary subunits. The subunit composition of the native channels is believed to be as follows. Rod: CNGA13/CNGB1a; Cone: CNGA32/CNGB32; Olfactory neurons: CNGA22/CNGA4/CNGB1b (Weitz et al., 2002; Zheng et al., 2002; Zhong et al., 2002; Peng et al., 2004; Zheng and Zagotta, 2004).

Further Reading

Bradley J, Reisert J, Frings S (2005). Regulation of cyclic nucleotide-gated channels. Curr Opin Neurobiol15: 343–349.

Brown RL, Strassmaier T, Brady JD, Karpen JW (2006). The pharmacology of cyclic nucleotide-gated channels: emerging from the darkness. Curr Pharm Des12: 3597–3613.

Craven KB, Zagotta WN (2006). CNG and HCN channels: two peas, one pod. Annu Rev Physiol68: 375–401.

Hofmann F, Biel M, Kaup UB (2005). International Union of Pharmacology. LI. Nomenclature and structure-function relationships of cyclic nucleotide-regulated channels. Pharmacol Rev57: 455–462.

Kaupp UB, Seifert R (2002). Cyclic nucleotide-gated ion channels. Physiol Rev82: 769–824.

Matulef K, Zagotta WN (2003). Cyclic nucleotide-gated ion channels. Annu Rev Cell Dev Biol19: 23–44.

Yu FH, Catterall WA (2004). The VGL-chanome: a protein superfamily specialized for electrical signaling and ionic homeostasis. Sci STKE2004 (253): re15.

References

Dryer SE, Henderson D (1991). Nature35: 756–758.

Fesenko EE et al. (1985). Nature313: 310–313.

Kaupp UB et al. (1989). Nature342: 762–766.

Nakamura T, Gold GH (1987). Nature325: 442–444.

Peng CH et al. (2004). Neuron42: 401–410.

Weitz D et al. (2002). Neuron36: 881–889.

Zheng J et al. (2002). Neuron36: 891–896.

Zheng J, Zagotta WN (2004). Neuron42: 411–421.

Zhong H et al. (2002). Nature420: 193–198.

Citation Information

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

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

Epithelial sodium (ENaC)

Overview: Epithelial sodium channels are responsible for sodium reabsorption by the epithelia lining the distal part of the kidney tubule, and fulfil similar functional roles in some other tissues such as the alveolar epithelium and the distal colon. This reabsorption of sodium is regulated by aldosterone, vasopressin and glucocorticoids, and is one of the essential mechanisms in the regulation of sodium balance, blood volume and blood pressure. ENaC expression is also vital for lung fluid balance (Hummler et al., 1996). Sodium reabsorption is suppressed by the ‘potassium-sparing’ diuretics amiloride and triamterene. The first ENaC subunit (α) was isolated by expression cloning, using a cDNA library derived from the colon of salt-deprived rats, as a current sensitive to inhibition by amiloride (Canessa et al., 1993). Two further subunits (β and γ) were identified by functional complementation of the α subunit (Canessa et al., 1994). A related δ subunit was later identified (Waldmann et al., 1995) that has a wider tissue distribution. ENaC subunits contain 2 putative TM domains connected by a large extracellular loop and short cytoplasmic amino- and carboxy-termini. The stoichiometry of the epithelial sodium channel in the kidney and related epithelia is thought to be predominantly a heterotetramer of 2α:1β:1γ subunits (Firsov et al., 1998).

NomenclatureEpithelial sodium channel (ENaC)
Ensembl IDHuman α subunit, ENSG00000111319; human β subunit, ENSG00000168447; human γ subunit, ENSG00000166828; human γ subunit, ENSG00000162572
Blockers (IC50) Functional characteristicsAmiloride (100-200 nM), benzamil (∼10 nM), triamterene (∼5 μM) (Canessa et al., 1994; Kellenberger et al., 2003) γ∼4-5 pS, PNa/PK >20; tonically open at rest; expression and ion flux regulated by circulating aldosterone-mediated changes in gene transcription. The action of aldosterone, which occurs in ‘early’ (1.5-3 h) and ‘late’ (6-24h) phases (Garty and Palmer, 1997) is competitively antagonised by spironolactone and its more active metabolite, canrenone. Glucocorticoids are important functional regulators in lung/airways and this control is potentiated by thyroid hormone; but the mechanism underlying such potentiation is unclear (Barker et al., 1990; Sayegh et al., 1999; Richard et al., 2004). The density of channels in the apical membrane, and hence GNa, can be controlled via both serum and glucocorticoid-regulated kinases (SGK1, 2 and 3) (Debonneville et al., 2001; Friedrich et al., 2003) and via cAMP/PKA (Morris and Schafer, 2002). ENaC is also constitutively activated by trypsin family serine peptidases (Planes and Caughey, 2007). Phosphatidylinositides such as PtIns(4,5)P2 and PtIns(3,4,5)P3) stabilise channel gating probably by binding to the β and γ ENaC subunits, respectively (Ma et al., 2007; Pochynyuk et al., 2007).

Data in the table refer to the 2αβγ heteromer. There are several human diseases resulting from mutations in ENaC subunits, or their regulation, most of which lead to over-expression or under-expression of the channel in epithelia. The best known of these is Liddle's syndrome, usually associated with gain of function mutations in the β and γ subunits that result in decreased down regulation of ENaC (Rotin, 2000; Staub et al., 1996). Pseudohypoaldosteronism type 1 (PHA-1) can occur through either mutations in the gene encoding the mineralocorticoid receptor, or mutations in genes encoding ENaC subunits (see Bonny and Hummler, 2000). Regulation of ENaC by phosphoinositides may underlie insulin-evoked renal Na+ retention that can complicate the clinical management of type 2 diabetes using insulin-sensitizing thiazolidinedione drugs (Guan et al., 2005).

Further Reading

Alvarez de la Rosa D, Canessa CM, Fyfe GK, Zhang P (2000). Structure and regulation of amiloride-sensitive sodium channels. Annu Rev Physiol62: 573–594.

Bonny O, Hummler E (2000). Dysfunction of epithelial sodium transport: from human to mouse. Kidney Int57: 1313–1318.

Garty H, Palmer LG (1997). Epithelial sodium channels: function, structure, and regulation. Physiol Rev77: 359–396.

Gormley K, Dong Y, Sagnella GA (2003). Regulation of the epithelial sodium channel by accessory proteins. Biochem J371: 1–14.

Hummler E, Vallon V (2005). Lessons from mouse mutants of epithelial sodium channel and its regulatory proteins. J Am Soc Nephrol16: 3160–3166.

Kellenberger S, Schild L. (2002). Epithelial sodium channel/degenerin family of ion channels: a variety of functions for a shared structure. Physiol Rev82: 735–767.

Ma HP, Chou CF, Wei SP, Eaton DC (2007). Regulation of the epithelial sodium channel by phosphatidylinositides: experiments, implications, and speculations. Pflügers Arch455: 169–180.

Planes C, Caughey GH (2007). Regulation of the epithelial Na+ channel by peptidases. Curr Top Dev Biol78: 23–46.

Pochynyuk O, Tong Q, Staruschenko A, Stockand JD (2007). Binding and direct activation of the epithelial Na+ channel (ENaC) by phosphatidylinositides. J Physiol580: 365–372.

Rossier BC, Pradervand S, Schild L, Hummler E (2002). Epithelial sodium channel and the control of sodium balance: interaction between genetic and environmental factors. Annu Rev Physiol.64: 877–897.

Sagnella GA, Swift PA (2006). The renal epithelial sodium channel: genetic heterogeneity and implications for the treatment of high blood pressure. Curr Pharm Des12: 2221–2234.

Schild L (2004). The epithelial sodium channel: from molecule to disease. Rev Physiol Biochem Pharmacol151: 93–107.

References

Barker PM et al. (1990). J Physiol424: 473–485.

Canessa CM et al. (1993). Nature361: 467–470.

Canessa CM et al. (1994). Nature367: 463–466.

Debonneville C et al. (2001). EMBO J20: 7052–7059.

Firsov D et al. (1998). EMBO J17: 344–352.

Friedrich B et al. (2003). Pflügers Arch445: 693–696.

Guan Y et al. (2005). Nature Med11: 861–866.

Hummler E et al. (1996). Nature Genet12: 325–328.

Kellenberger S et al. (2003). Mol Pharmacol64: 848–856.

Morris RG, Schafer JA (2002). J Gen Physiol120: 71–85.

Rotin D (2000). Curr Opin Nephrol Hypertens9: 529–534.

Richard K et al. (2004). FEBS Lett576: 339–342.

Sayegh R et al. (1999). J Biol Chem274: 12431–12437.

Staub O et al. (1996). EMBO J15: 2371–2380.

Waldmann R et al. (1995). J Biol Chem270: 27411–27414.

Citation Information

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

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

Hyperpolarisation-activated, cyclic nucleotide-gated (HCN)

Overview: The hyperpolarisation-activated, cyclic nucleotide-gated (HCN) channels are cation channels that are activated by hyperpolarisation at voltages negative to ∼ −50 mV. The cyclic nucleotides cAMP and cGMP directly activate the channels and shift the activation curves of HCN channels to more positive voltages, thereby enhancing channel activity. HCN channels underlie pacemaker currents found in many excitable cells including cardiac cells and neurons (DiFrancesco, 1993; Pape, 1996). In native cells, these currents have a variety of names, such as Ih, Iq and If. The four known HCN channels have six transmembrane domains and form tetramers. It is believed that the channels can form heteromers with each other, as has been shown for HCN1 and HCN4 (Altomare et al., 2003). A standardised nomenclature for HCN channels has been proposed by the NC-IUPHAR subcommittee on voltage-gated ion channels (see Hofmann et al., 2005).

NomenclatureHCN1HCN2HCN3HCN4
Ensembl IDENSG00000164588ENSG00000099822ENSG00000143630ENSG00000138622
ActivatorscAMP>cGMP (both weak)cAMP>cGMPcAMP>cGMP
InhibitorsCs, ZD7288Cs+, ZD7288Cs+, ZD7288Cs+, ZD7288

HCN channels are permeable to both Na+ and K+ ions, with a Na+/K+ permeability ratio of about 0.2. Functionally, they differ from each other in terms of time constant of activation with HCN1 the fastest, HCN4 the slowest and HCN2 and HCN3 intermediate. The compounds ZD7288 (BoSmith et al., 1993) and ivabradine (Bucchi et al., 2002) have proven useful in identifying and studying functional HCN channels in native cells.

Abbreviations: Ivabradine (S16257-2), (3-(3-{[((7S)-3,4-dimethoxybicyclo [4,2,0] octa-1,3,5-trien7-yl) methyl] methylamino} propyl)-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-benzazepin-2-one hydrochloride; ZD7288, [4-(N-ethyl-N-phenyl-amino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride

Further Reading

Baruscotti M, Bucchi A, DiFrancesco D (2005). Physiology and pharmacology of the cardiac pacemaker (“funny”) current. Pharmacol Ther107: 59–79.

Biel M, Ludwig A, Zong X, Hofmann F (1999). Hyperpolarisation-activated cation channels: a multi-gene family. Rev Physiol Biochem Pharmacol136: 165–181.

Biel M, Schneider A, Wahl C (2002). Cardiac HCN channels: structure, function and modulation. Trends Cardiovasc Med12: 206–213.

Bois P, Guinamard R, Chemaly AE, Faivre JF, Bescond J (2007). Molecular regulation and pharmacology of pacemaker channels. Curr Pharm Des13: 2338–2349.

Craven KB, Zagotta WN (2006). CNG and HCN channels: two peas, one pod. Annu Rev Physiol68: 375–401.

DiFrancesco D (1993). Pacemaker mechanisms in cardiac tissue. Annu Rev Physiol55: 455–472.

DiFrancesco D, Camm JA (2004). Heart rate lowering by specific and selective I–f current inhibition with ivabradine - a new therapeutic perspective in cardiovascular disease. Drugs64: 1757–1765.

Hofmann F, Biel M, Kaupp UB (2005). International Union of Pharmacology. LI. Nomenclature and structure-function relationships of cyclic nucleotide-regulated channels. Pharmacol Rev57: 455–462.

Kaupp UB, Seifert R (2001). Molecular diversity of pacemaker ion channels. Annu Rev Physiol63: 235–257.

Meldrum BS, Rogawski MA (2007). Molecular targets for antiepileptic drug development. Neurotherapeutics4: 18–61.

Pape HC (1996). Queer current and pacemaker: the hyperpolarisation-activated cation current in neurons. Annu Rev Physiol58: 299–327.

Yu FH, Catterall WA (2004). The VGL-chanome: a protein superfamily specialized for electrical signaling and ionic homeostasis. Sci STKE2004 (253): re15.

References

Altomare C et al. (2003). J Physiol549: 347–359.

Bosmith RE et al. (1993). Br J Pharmacol110: 343–349.

Bucchi A et al. (2002). J Gen Physiol120: 1–13.

Citation Information

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

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

IP3 receptor

Overview: The inositol 1,4,5-trisphosphate receptors (IP3R) are ligand-gated Ca2+-release channels on intracellular Ca2+ store sites (such as the endoplasmic reticulum). They are responsible for the mobilization of intracellular Ca2+ stores and play an important role in intracellular Ca2+ signalling in a wide variety of cell types. Three different gene products (types I-III) have been isolated, which assemble as large tetrameric structures. IP3Rs are closely associated with certain proteins: calmodulin and FKBP (and calcineurin via FKBP). They are phosphorylated by PKA, PKC, PKG and CaMKII.

NomenclatureIP3R1IP3R2IP3R3
Other namesINSP3R1INSP3R2INSP3R3
Ensembl IDENSG00000150995ENSG00000123104ENSG00000096433
Endogenous activatorsIns(1,4,5)P3 (nM–μM), cytosolic Ca2+ (<750 μM), cytosolic ATP (<mM)Ins(1,4,5)P3 (nM–μM), cytosolic Ca2+ (<mM)Ins(1,4,5)P3 (nM–μM), cytosolic Ca2+ (<mM)
Pharmacological activatorsInsP3 analogues including Ins(2,4,5)P3, adenophostin A (nM)InsP3 analogues including Ins(2,4,5)P3, adenophostin A (nM)
AntagonistsXestospongin C (μM), phosphatidylinositol 4,5-bisphosphate (μM), caffeine (mM), heparin (μg/ml), decavanadate (μM), calmodulin at high cytosolic Ca2+Heparin (μg/ml), decavanadate (μM)Heparin (μg/ml), decavanadate (μM)
Functional characteristicsCa2+: (PBa/PK∼6) single-channel conductance ∼70pS (50mM Ca2+)Ca2+: single-channel conductance∼70pS (50mM Ca2+), ∼390 pS (220mM Cs+)Ca2+: single-channel conductance∼88pS (55 mM Ba2+)

The absence of a modulator of a particular isoform of receptor indicates that the action of that modulator has not been determined, not that it is without effect.

Abbreviation: FKBP, FK506-binding protein

Further Reading

Berridge MJ, Lipp P, Bootman MD (2000). The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol1: 11–21.

Bolton TB (2006). Calcium events in smooth muscles and their interstitial cells: physiological roles of sparks. J Physiol570: 5–11.

Bootman MD, Berridge MJ, Roderick HL (2002). Calcium signalling: more messengers, more channels, more complexity. Curr Biol12: R563–R565.

Bosanac I, Michikawa T, Mikoshiba K, Ikura M (2004). Structural insights into the regulatory mechanism of IP3 receptor. Biochim Biophys Acta1742: 89–102.

Bultynck G, Sienaert I, Parys JB, Callewaert G, De Smedt H, Boens N et al. (2003). Pharmacology of inositol trisphosphate receptors. Pflügers Arch445: 629–642.

Choe CU, Ehrlich BE (2006). The inositol 1,4,5-triphosphate receptor (IP3R) and its regulators: sometimes good and sometimes bad team work. Sci STKE2006: re15.

Foskett JK, White C, Cheung KH, Mak DO (2007). Inositol trisphosphate receptor Ca2+ release channels. Physiol Rev87: 593–658.

Mikoshiba K (2007). The IP3 receptor/Ca2+ channel and its cellular function. Biochem Soc Symp74: 9–22.

Nahorski SR (2006). Pharmacology of intracellular signalling pathways. Br J Pharmacol147 (Suppl 1): S38–S45.

Patel S, Joseph SK, Thomas AP (2009). Molecular properties of inositol 1,4,5-trisphosphate receptors. Cell Calcium25: 247–264.

Patterson RL, Boehning D, Snyder SH (2004). Inositol 1,4,5-triphosphate receptors as signal integrators. Annu Rev Biochem73: 437–465.

Taylor CW, Traynor D (1995). Calcium and inositol trisphosphate receptors. J Membr Biol145: 109–118.

Verkhratsky A (2005). Physiology and pathophysiology of the calcium store in the endoplasmic reticulum of neurons. Physiol Rev85: 201–279.

Vermassen E, Parys JB, Mauger J-P (2004). Subcellular distribution of the inositol 1,4,5-triphosphate receptors: functional relevance and molecular determinants. Biol Cell96: 3–17.

Citation Information

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

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

Potassium

Overview: Potassium channels are fundamental regulators of excitability. They control the frequency and the shape of action potential waveform, the secretion of hormones and neurotransmitters and cell membrane potential. Their activity may be regulated by voltage, calcium and neurotransmitters (and the signalling pathways they stimulate). They consist of a primary pore-forming αsubunit often associated with auxiliary regulatory subunits. Since there are over 70 different genes encoding K channels αsubunits in the human genome, it is beyond the scope of this guide to treat each subunit individually. Instead, channels have been grouped into families and subfamilies based on their structural and functional properties. Due to space constraints, the Ensembl ID for only one member of each subfamily is given. Ensembl information for the other subfamily members can be found from links therein. The three main families are the 2TM (two transmembrane domain), 4TM and 6TM families. A standardised nomenclature for potassium channels has been proposed by the NC-IUPHAR subcommittees on potassium channels (see Goldstein et al., 2005; Gutman et al., 2005; Kubo et al., 2005; Wei et al., 2005).

The 2TM family of K channels

The 2TM domain family of K channels are also known as the inward-rectifier K channel family. This family includes the strong inward-rectifier K channels (KIR2.x), the G-protein-activated inward-rectifier K channels (KIR3.x) and the ATP-sensitive K channels (KIR6.x, which combine with sulphonylurea receptors (SUR)). The pore-forming αsubunits form tetramers, and heteromeric channels may be formed within subfamilies (e.g. KIR3.2 with KIR3.3).

Subfamily groupKIR1.xKIR2.xKIR3.xKIR4.x
SubtypesKIR1.1 (ROMK1)KIR2.1–2.4 (IRK1–4)KIR3.1–3.4 (GIRK1–4)KIR4.1–4.2
Ensembl IDENSG00000151704 (KIR1.1)ENSG00000123700 (KIR2.1)ENSG00000162989 (KIR3.1)ENSG00000177807 (KIR4.1)
ActivatorsPIP2, Gβγ
Inhibitors[Mg2+]i, polyamines (internal)
Functional characteristicInward-rectifier currentIK1 in heart, ‘strong’ inward-rectifier currentG-protein-activated inward-rectifier currentInward-rectifier current
Subfamily groupKIR5.xKIR6.xKIR7.x
SubtypesKIR5.1KIR6.1–6.2 (KATP)KIR7.1
Ensembl IDENSG00000153822 (KIR5.1)ENSG00000121361 (KIR6.1)ENSG00000115474 (KIR7.1)
ActivatorsMinoxidil, cromakalim, diazoxide, nicorandil
InhibitorsTolbutamide, glibenclamide
Functional characteristicInward-rectifier currentATP-sensitive, inward-rectifier currentInward-rectifier current
Associated subunitsSUR1, SUR2A, SUR2B

The 4TM family of K channels

The 4TM family of K channels are thought to underlie many leak currents in native cells. They are open at all voltages and regulated by a wide array of neurotransmitters and biochemical mediators. The primary pore-forming α subunit contains two pore domains (indeed, they are often referred to as two-pore domain K channels or K2P) and so it is envisaged that they form functional dimers rather than the usual K channel tetramers. There is some evidence that they can form heterodimers within subfamilies (e.g. K2P3.1 with 2P9.1). There is no current, clear, consensus on nomenclature of 4TM K channels, nor on the division into subfamilies (see Goldstein et al., 2005). The suggested division into subfamilies, below, is based on similarities in both structural and functional properties within subfamilies.

Subfamily group‘TWIK’‘TREK’‘TASK’‘TALK’‘THIK’‘TRESK’
Subtypes2P1.1 (TWIK1)2P2.1 (TREK1)2P3.1 (TASK1)2P16.1 (TALK1)2P13.1 (THIK1)2P18.1 (TRESK1)
 2P6.1 (TWIK2)2P10.1 (TREK2)2P9.1 (TASK3)2P5.1 (TASK2)2P12.1 (THIK2) 
 2P7.1 (KNCK7)2P4.1 (TRAAK)2P15.1 (TASK5)2P17.1 (TASK4)  
Ensembl IDENSG0000ENSG00000ENSG0000ENSG0000ENSG0000ENSG0000
 0135750 (2P1.1)082482 (2P2.1)0171301 (2P3.1)0164626 (2P5.1)0152315 (2P13.1)0186795 (2P18.1)
ActivatorsHalothane (not TRAAK), riluzole stretch, heat, arachidonic acid, acid pHiHalothane alkaline pHo (2P3.1)Alkaline pHo
InhibitorsAcid pHiAnandamide (2P3.1, 2P9.1) ruthenium red (2P9.1) acid pHoHalothaneArachidonic acid

The K2P7.1, K2P15.1 and K2P12.1 subtypes, when expressed in isolation, are nonfunctional. All 4TM channels are insensitive to the classical potassium channel blockers TEA and 4-AP, but are blocked to varying degrees by Ba2+ ions.

The 6TM family of K channels

The 6TM family of K channels comprises the voltage-gated KV subfamilies, the KCNQ subfamily the EAG subfamily (which includes herg channels), the Ca2+-activated Slo subfamily (actually with 7TM) and the Ca2+-activated SK subfamily. As for the 2TM family, the pore-forming α subunits form tetramers and heteromeric channels may be formed within subfamilies (e.g. KV1.1 with KV1.2; KCNQ2 with KCNQ3).

Subfamily groupKV1.xKV2.xKV3.xKV4.x
SubtypesKV1.1–KV1.8KV2.1–2.2KV3.1–3.4KV4.1–4.3
 Shaker-relatedShab-relatedShal-relatedShaw-related
Ensembl IDENSG00000111262 (KV1.1)ENSG00000158445 (KV2.1)ENSG00000129159 (KV3.1)ENSG00000102057 (KV4.1)
InhibitorsTEA potent (1.1), TEA moderate (1.3, 1.6), 4-AP potent (1.4), α-dendrotoxin (1.1, 1.2, 1.6), margatoxin (1.1, 1.2, 1.3), noxiustoxin (1.2, 1.3)TEA moderateTEA potent, 4-AP potent (3.1, 3.2), BDS-1 (3.4)
Functional characteristicsKV(1.1–1.3, 1.5–1.8), KA (1.4)KV (2.1)KV (3.1, 3.2), KA (3.3, 3.4)KA
Associated subunitsKV β1, KV β2KV5.1, KV6.1–6.3, KV8.1, KV9.1–9.3MiRP2 (KV3.4)KChIP, KChAP
Subfamily groupKV7.x (‘KCNQ’)KV10.x, KV11.x, KV12.x (‘EAG’)KCa1.x, KCa4.x, KCa5.x (‘Slo’)KCa2.x, KCa3.x (‘SK’)
SubtypesKV.7.1–7.5 (KCNQ1-5)KV10.1-10.2 (eag1–2) KV11.1–11.3 (erg1-3, herg 1–3) KV12.1–12.3 (elk1-3)KCa1.1, KCa4.1–4.2, KCa5.1 Slo (BK), Slack, SlickKCa2.1–2.3 (SK1–SK3) KCa3.1 (SK4, IK)
Ensembl IDENSG00000053918 (KV7.1)ENSG00000143473 (KV10.1)ENSG00000156113 (KCa1.1)ENSG00000105642 (KCa2.1)
ActivatorsRetigabine (KV.7.2,–5)NS004, NS1619
InhibitorsTEA (KV.7.2, 7.4), XE991 (KV.7.1, 7.2, 7.4, 7.5), linopirdineE-4031 (KV11.1), astemizole (KV11.1), terfenadine (KV11.1)TEA, charybdotoxin, iberiotoxinCharybdotoxin (KCa3.1), apamin (KCa2.1–2.3)
Functional characteristicKV7.1—cardiac IKS KV7.2/7.3—M currentKV11.1—cardiac IKRMaxi KCa KNa (slack & slick)SKCa (KCa2.1–2.3) IKCa (KCa3.1)
Associated subunitsminK, MiRP2 (KV.7.1)minK, MiRP1 (erg1)KCNMB1-4 (KCa1.1)

Abbreviations: 4-AP, 4-aminopyridine; BDS-1, blood depressing substance 1; E4031, 1-(2-(6-methyl-2-pyridyl)ethyl)-4-(4-methylsulphonyl aminobenzoyl)piperidine; NS004, 1-(2-hydroxy-5-chlorophenyl)-5-trifluromethyl-2-benzimidazolone; NS1619, 1-(2′-hydroxy-5′-trifluro-methylphenyl)-5-trifluro-methyl-2 (3H)benzimidazolone; PIP2, phosphatidylinositol 4,5, bisphosphate; TEA, tetraethylammonium; XE991, 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracene

Further Reading

Aguilar-Bryan L, Clement JP, Gonzalez G, Kunjilwar K, Babenko A, Bryan J (1998). Toward understanding the assembly and structure of KATP channels. Physiol Rev78: 227–245.

Ashcroft FM, Gribble FM (1998). Correlating structure and function in ATP-sensitive K+ channels. Trends Neurosci21: 288–294.

Bauer CK, Schwartz JR (2001). Physiology of EAG channels. J Membr Biol182: 1–15.

Bean BP (2001). The action potential in mammalian central neurons. Nat Rev Neurosci8: 451–465.

Bezanilla F (2000). The voltage sensor in voltage-dependent ion channels. Physiol Rev80: 555–592.

Dalby-Brown W, Hansen HH, Korsgaard MP, Mirza N, Olesen SP (2006). K(v) channels: function, pharmacology and channel modulators. Curr Top Med Chem6: 999–1023.

Goldstein SAN, Bayliss DA, Kim D, Lesage F, Plant LD, Rajan S (2005). International union of pharmacology. LV. Nomenclature and molecular relationships of Two-P potassium channels. Pharmacol Rev57: 527–540.

Goldstein SAN, Bockenhauer D, O'Kelly I, Zilberberg N (2001). Potassium leak channels and the KCNK family of two-P domain subunits. Nat Rev Neurosci2: 175–184.

Gutman GA, Chandy KG, Grissmer S, Lazdunski M, McKinnon D, Pardo LA et al. (2005). International union of pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels. Pharmacol Rev57: 473–508.

Hansen JB (2006). Towards selective Kir6.2/SUR1 potassium channel openers, medicinal chemistry and therapeutic perspectives. Curr Med Chem13: 26–376.

Honore E (2007). The neuronal background K2P channels: focus on TREK1. Nature Rev Neurosci8: 251–261.

Jenkinson DH (2006). Potassium channels—multiplicity and challenges. Br J Pharmacol147 (Suppl 1): S63–S71.

Judge SI, Bever Jr CT (2006). Potassium channel blockers in multiple sclerosis: neuronal Kv channels and effects of symptomatic treatment. Pharmacol Ther111: 224–259.

Kaczorowski GJ, Garcia ML (1999). Pharmacology of voltage-gated and calcium-activated potassium channels. Curr Opin Chem Biol3: 448–458.

Kobayashi T, Ikeda K (2006). G protein-activated inwardly-rectifying potassium channels as potential therapeutic targets. Curr Pharm Des12: 4513–4523.

Kubo Y, Adelman JP, Clapham DE, Jan LY, Karschin A, Kurachi Y et al. (2005). International union of pharmacology. LIV. Nomenclature and molecular relationships of inwardly rectifying potassium channels. Pharmacol Rev57: 509–526.

Lawson K, McKay NG (2006). Modulation of potassium channels as a therapeutic approach. Curr Pharm Des12: 459–470.

Lesage F (2003). Pharmacology of neuronal background potassium channels. Neuropharmacology44: 1–7.

Lewis RJ, Garcia ML (2003). Therapeutic potential of venom peptides. Nat Rev Drug Discov2: 790–802.

Mannhold R (2006). Structure-activity relationships of K(AATP) channel openers. Curr Top Med Chem6: 1031–1047.

Mathie A, Veale EL (2007). Therapeutic potential of neuronal two pore domain potassium channel modulators. Curr Opin Invest Drugs8: 555–562.

Miller C (2003). A charged view of voltage-gated ion channels. Nat Struct Biol10: 422–424.

Nichols CG, Lopatin AN (1997). Inwardly rectifying potassium channels. Annu Rev Physiol59: 171–191.

O'Connell AD, Morton MJ, Hunter M (2002). Two-pore domain K+ channels—molecular sensors. Biochem Biophys Acta—Biomembrane1566: 152–161.

Reimann F, Ashcroft FM (1999). Inwardly rectifying potassium channels. Curr Opin Cell Biol11: 503–508.

Robbins J (2001). KCNQ potassium channels: physiology, pathophysiology and pharmacology. Pharmacol Ther90: 1–19.

Salkoff L, Butler A, Ferreira G, Santi C, Wei A (2006). High-conductance potassium channels of the SLO family. Nature Rev Neurosci7: 921–931.

Sanguinetti MC (2000). Maximal function of minimal K+ channel subunits. Trends Pharmacol Sci21: 199–201.

Seino S, Miki T (2003). Physiological and pathophysiological roles of ATP-sensitive K+ channels. Prog Biophys Mol Biol81: 133–176.

Stanfield PR, Nakajima S, Nakajima Y (2002). Constitutively active and G-protein coupled inward rectifier K+ channels: Kir2.0 and Kir3.0. Rev Physiol Biochem Pharmacol145: 47–179.

Stocker M (2004). Ca2+-activated K+ channels: molecular determinants and function of the SK family. Nat Rev Neurosci5: 758–770.

Trimmer JS, Rhodes KJ (2004). Localisation of voltage-gated ion channels in mammalian brain. Annu Rev Physiol66: 477–519.

Wang H, Tang Y, Wang L, Long CL, Zhang YL (2007). ATP-sensitive potassium channel openers and 2,3-dimethyl-2-butylamine derivatives. Curr Med Chem14: 133–155.

Wei AD, Gutman GA, Aldrich R, Chandy KG, Grissmer S, Wulff H (2005). International Union of Pharmacology. LII. Nomenclature and molecular relationships of calcium-activated channels. Pharmacol Rev57: 463–472.

Witchel HJ (2007). The hERG potassium channel as a therapeutic target. Expert Opin Ther Targets11: 321–336.

Yellen G (2002). The voltage-gated potassium channels and their relatives. Nature419: 35–42.

Yu FH, Catterall WA (2004). The VGL-chanome: a protein superfamily specialized for electrical signaling and ionic homeostasis. Sci STKE2004 (253): re15.

Citation Information

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

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

Ryanodine receptor

Overview: The ryanodine receptors (RyRs) are found on intracellular Ca2+ storage/release organelles. The family of RyR genes encodes three highly related Ca2+ release channels: RyR1, RyR2 and RyR3, which assemble as large tetrameric structures. These RyR channels are ubiquitously expressed in many types of cells and participate in a variety of important Ca2+ signaling phenomena (neurotransmission, secretion, etc.). In addition to the three mammalian isoforms described below, various nonmammalian isoforms of the ryanodine receptor have been identified and these are discussed in Sutko and Airey (1996). The function of the ryanodine receptor channels may also be influenced by closely associated proteins such as the tacrolimus (FK506)-binding protein, calmodulin (Yamaguchi et al., 2003), triadin, calsequestrin, junctin and sorcin, and by protein kinases and phosphatases.

NomenclatureRyR1RyR2RyR3
Ensembl IDENSG00000196218ENSG00000198626ENSG00000198838
Endogenous activatorsDepolarisation via DHP receptor, cytosolic Ca2+ (μM), cytosolic ATP (mM), luminal Ca2+, calmodulin at low cytosolic Ca2+, CaM kinase, PKACytosolic Ca2+ (μM), cytosolic ATP (mM), luminal Ca2+, CaM kinase, PKACytosolic Ca2+ (μM), cytosolic ATP (mM), calmodulin at low cytosolic Ca2+
Pharmacological activatorsRyanodine (nM-μM), caffeine (mM), suramin (μM)Ryanodine (nM–μM), caffeine (mM), suramin (μM)Ryanodine (nM–μM), caffeine (mM)
AntagonistsCytosolic Ca2+ (>100 μM), cytosolic Mg2+ (mM), calmodulin at high cytosolic Ca2+ dantroleneCytosolic Ca2+ (>1 mM), cytosolic Mg2+ (mM), calmodulin at high cytosolic Ca2+Cytosolic Ca2+ (>1 mM), cytosolic Mg2+ (mM), calmodulin at high cytosolic Ca2+, dantrolene
Channel blockersRyanodine (>100 μM), ruthenium red, procaineRyanodine (>100 μM), ruthenium red, procaineRuthenium red
Functional characteristicsCa2+: (PCa/PK∼6) single-channel conductance: ∼90 pS (50 mM Ca2+), 770 pS (200 mM K+)Ca2+: (PCa/PK∼6) single-channel conductance: ∼90 pS (50 mM Ca2+), 720 pS (210 mM K+)Ca2+: (PCa/PK∼6) single-channel conductance: ∼140 pS (250 mM Ca2+), 777 pS (250 mM K+)

The modulators of channel function included in this table are those most commonly used to identify ryanodine-sensitive Ca2+ release pathways. Numerous other modulators of ryanodine receptor/channel function can be found in the reviews listed below. The absence of a modulator of a particular isoform of receptor indicates that the action of that modulator has not been determined, not that it is without effect. The potential role of cyclic ADP ribose as an endogenous regulator of ryanodine receptor channels is controversial. A region of RyR likely to be involved in ion translocation and selection has been identified (Zhao et al., 1999; Gao et al., 2000).

Further Reading

Berridge M, Bootman MD, Roderick HL (2003). Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol4: 517–529.

Berridge MJ, Lipp P, Bootman MD (2000). The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol1: 11–21.

Bolton TB (2006). Calcium events in smooth muscles and their interstitial cells: physiological roles of sparks. J Physiol570: 5–11.

Bouchard R, Pattarini E, Geiger JD (2003). Presence and functional significance of presynaptic ryanodine receptors. Prog Neurobiol69: 391–418.

Collin T, Marty A, Llano I (2005). Presynaptic calcium stores and synaptic transmission. Curr Opin Neurobiol15: 275–281.

Dulhunty AF, Beard NA, Pouliquin P, Casarotto MG (2007). Agonists and antagonists of the cardiac ryanodine receptor: potential therapeutic agents? Pharmacol Ther113: 247–263.

Eisner A, Diaz ME, O'Neill SC, Trafford AW (2004). Physiology and pathological modulation of ryanodine receptor function in cardiac muscle. Cell Calcium35: 583–589.

Fill M, Copello JA (2002). Ryanodine receptor calcium release channels. Physiol. Rev82: 893–922.

Meissner G (2004). Molecular regulation of cardiac ryanodine receptor ion channel. Cell Calcium35: 621–628.

Nahorski SR (2006). Pharmacology of intracellular signalling pathways. Br J Pharmacol147 (Suppl 1): S38–S45.

Ross D, Sorrentino V (2002). Molecular genetics of ryanodine receptors Ca2+ release channels. Cell Calcium32: 307–319.

Shoshan-Barmatz V, Ashley RH (1998). The structure, function and cellular regulation of ryanodine-sensitive Ca2+-release channels. Int Rev Cytol183: 185–270.

Sitsapesan R, Williams AJ (1998). The Structure and Function of Ryanodine Receptors. London: Imperial College Press.

Sutko JL, Airey JA (1996). Ryanodine Ca2+ release channels: does diversity in form equal diversity in function? Physiol Rev76: 1027–1071.

Sutko JL, Airey JA, Welch W, Ruest L (1997). The pharmacology of ryanodine and related compounds. Pharmacol Rev49: 53–98.

Taur Y, Frishman WH (2005). The cardiac ryanodine receptor (RyR2) and its role in heart disease. Cardiol Rev13: 142–146.

Verkhratsky A (2005). Physiology and pathophysiology of the calcium store in the endoplasmic reticulum of neurons. Physiol Rev85: 201–279.

Zucchi R, Ronca-Testoni S (1997). The sarcoplasmic reticulum Ca2+ channel/ryanodine receptor: modulation by endogenous effectors, drugs and disease states. Pharmacol Rev49: 1–51.

References

Gao L et al. (2000). Biophys J79: 828–840.

Yamaguchi N et al. (2003). J Biol Chem278: 23480–23486.

Zhao MC et al. (1999). J Biol Chem274: 25971–25974.

Citation Information

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

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

Sodium (voltage-gated)

Overview: Sodium channels are voltage-gated sodium-selective ion channels present in the membrane of most excitable cells. Sodium channels comprise of one pore-forming αsubunit, which may be associated with either one or two βsubunits (Isom, 2001). α-Subunits consist of four homologous domains (I–IV), each containing six transmembrane segments (S1–S6) and a pore-forming loop. The positively charged fourth transmembrane segment (S4) acts as a voltage sensor and is involved in channel gating. Auxiliary β1, β2, β3 and β4 subunits consist of a large extracellular N-terminal domain, a single transmembrane segment and a shorter cytoplasmic domain.

The nomenclature for sodium channels was proposed by Goldin et al. (2000) and approved by the NC-IUPHAR subcommittee on sodium channels (Catterall et al., 2005).

NomenclatureNaV1.1NaV1.2NaV1.3NaV1.4NaV1.5
Alternative namesBrain type IBrain type IIBrain type IIIμ1, SkM1h1, SkM II, cardiac
Ensembl IDENSG00000144285ENSG00000136531ENSG00000153253ENSG00000007314ENSG00000183873
ActivatorsVeratridine, batrachotoxinVeratridine, batrachotoxinVeratridine, batrachotoxinVeratridine, batrachotoxinVeratridine, batrachotoxin
BlockersTetrodotoxin (10 nM), saxitoxinTetrodotoxin (10 nM), saxitoxinTetrodotoxin (2–15 nM) saxitoxinμ-Conotoxin GIIIA, tetrodotoxin (5nM), saxitoxinTetrodotoxin (2 μM)
Functional characteristicFast inactivation (0.7 ms)Fast inactivation (0.8 ms)Fast inactivation (0.8 ms)Fast inactivation (0.6 ms)Fast inactivation (1 ms)
NomenclatureNaV1.6NaV1.7NaV1.8NaV1.9
Alternative namesPN4, NaCH6PN1, NaSSNS, PN3NaN, SNS2
Ensembl IDENSG00000196876ENSG00000169432ENSG00000185313ENSG00000168356
ActivatorsActivatratridine, batrachotoxinVeratridine, batrachotoxin
BlockersTetrodotoxin (6 nM), saxitoxinTetrodotoxin (4 nM), saxitoxinTetrodotoxin (60 μM)Tetrodotoxin (40 μM)
Functional characteristicFast inactivation (1 ms)Fast inactivation (0.5 ms)Slow inactivation (6 ms)Slow inactivation (16 ms)

Sodium channels are also blocked by local anaesthetic agents, antiarrythmic drugs and antiepileptic drugs. There are two clear functional fingerprints for distinguishing different subtypes. These are sensitivity to tetrodotoxin (NaV1.5, NaV1.8 and NaV1.9 are much less sensitive to block) and rate of inactivation (NaV1.8 and particularly NaV1.9 inactivate more slowly).

Further Reading

Baker MD, Wood JN (2001). Involvement of Na+ channels in pain pathways. Trends Pharmacol Sci22: 27–31.

Bean BP (2007). The action potential in mammalian central neurons. Nat Rev Neurosci8: 451–465.

Cantrell AR, Catterall WA (2001). Neuromodulation of Na+ channels: an unexpected form of cellular plasticity. Nat Rev Neurosci2: 397–407.

Catterall WA (2005). Structure and function of voltage-gated ion channels. Annu Rev Biochem64: 493–531.

Catterall WA (2000). From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron26: 13–25.

Catterall WA, Goldin AL, Waxman SG (2005). International Union of Pharmacology. XLVII. Nomenclature and structure function relationships of voltage-gated sodium channels. Pharmacol Rev57: 397–409.

Fozzard HA, Hanck DA (1996). Structure and function of voltage-dependent sodium channels – comparison of brain-II and cardiac isoforms. Physiol Rev76: 887–926.

Fozzard HA, Lee PJ, Lipkind GM (2005). Mechanism of local anesthetic drug action on voltage-gated sodium channels. Curr Pharm Des11: 2671–2686.

George AL (2005). Inherited disorders of voltage-gated sodium channels. J Clin Invest115: 1990–1999.

Goldin AL (2001). Resurgence of sodium channel research. Annu Rev Physiol63: 874–894.

Isom LL (2001). Sodium channel beta subunits: anything but auxiliary. Neuroscientist7: 42–54.

Kyle DJ, Ilyin VI (2007). Sodium channel blockers. J Med Chem50: 2583–2588.

Lai J, Porreca F, Hunter JC, Gold MS (2004). Voltage-gated sodium channels and hyperalgesia. Ann Rev Pharmacol Toxicol44: 371–397.

Lewis RJ, Garcia ML (2003). Therapeutic potential of venom peptides. Nat Rev Drug Discov2: 790–802.

Priest BT, Kaczorowski GJ (2007). Blocking sodium channels to treat neuropathic pain. Expert Opin Ther Targets11: 291–306.

Priestley T (2004). Voltage-gated sodium channels and pain. Curr Drug Targets CNS Neurol Disord3: 441–456.

Terlau H, Olivera BM (2004). Conus venoms: a rich source of novel ion channel-targeted peptides. Physiol Rev84: 41–68.

Trimmer JS, Rhodes KJ (2004). Localisation of voltage-gated ion channels in mammalian brain. Annu Rev Physiol66: 477–519.

Wood JN, Boorman J (2005). Voltage-gated sodium channel blockers; target validation and therapeutic potential. Curr Top Med Chem5: 529–537.

Yu FH, Catterall WA (2004). The VGL-chanome: a protein superfamily specialized for electrical signaling and ionic homeostasis. Sci STKE2004 (253): re15.

Reference

Goldin AL et al. (2000). Neuron28: 365–368.

Citation Information

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

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

Transient receptor potential (TRP) cation

Overview: The TRP superfamily of cation channels (nomenclature agreed by NC-IUPHAR; Clapham et al., 2003), whose founder member is the Drosophila Trp channel, can be divided, in mammals, into six families; TRPC, TRPM, TRPV, TRPA, TRPP and TRPML based on amino acid homologies (see Clapham, 2003; Delmas et al., 2004; Moran et al., 2004, Montell, 2005, Nilius and Voets, 2005; Pedersen et al., 2005; Voets et al., 2005; Owsianik et al., 2006a; Minke, 2006; Ramsey et al., 2006; Venkatachalam and Montell, 2007). TRP subunits contain six putative transmembrane domains and assemble as homo- or hetero-tetramers to form cation selective channels with varied permeation properties (reviewed by Owsianik et al., 2006b). The TRPC (‘Canonical’) and TRPM (‘Melastatin’) subfamilies consist of seven and eight different channels, respectively (i.e., TRPC1-TRPC7 and TRPM1-TRPM8). The TRPV (‘Vanilloid’) subfamily comprises six members (TRPV1-TRPV6) whereas the TRPA (Ankyrin) subfamily has only one mammalian member (TRPA1). The TRPP (‘Polycystin’) and TRPML (‘Mucolipin’) families are not fully characterised, and the tables below are thus incomplete. Established, or potential, physiological functions of the individual members of the TRP families are discussed in detail in the recommended reviews and are only briefly mentioned here. The established, or potential, involvement of TRP channels in disease is reviewed in Kiselyov et al. (2007a) and Nilius et al. (2005a, 2007).

TRPC family: Members of the TRPC subfamily (reviewed by Vazquez et al., 2004, Freichel et al., 2005; Pedersen et al., 2005; Putney, 2005), on the basis of sequence homology and similarities in function, fall into four subfamilies: TRPC1, TRPC2, TRPC3/6/7 and TRPC4/5. TRPC2 (not tabulated) is a pseudogene in man. All TRPC channels have been proposed to act as store-operated channels (SOCs), activated by depletion of intracellular calcium stores (reviewed by Nilius, 2003a; Vazquez et al., 2004a, Pedersen et al., 2005; Worley et al., 2007; see also http://www.stke.org/cgi/content/full/sigtrans;2004/243). However, there is conflicting evidence that TRPC1, TRPC4/5 and TRPC3/6/7 can function as receptor-operated channels that are mostly insensitive to store depletion (reviewed by Plant and Schaefer, 2003; Vazquez et al., 2004a; Trebak et al., 2007). TRPC4-/- mice demonstrate an impaired store-operated calcium current in vascular endothelial cells, suggesting that this protein forms, or is an essential component of, a store-operated Ca2+ channel (SOC) in vivo (Freichel et al., 2001; Tiruppathi et al., 2002). The relationship of other TRPC channels to endogenous SOCs is less clear at present, although TRPC1 and TRPC5 appear to be components of a cation channel within the CNS (Strübing et al., 2001). TRPC6 is essential for the function of a cation channel-mediated entry of Ca2+ into vascular smooth muscle cells subsequent to α-adrenoceptor activation (Inoue et al., 2001).

NomenclatureTRPC1TRPC3TRPC4
Other namesTRP1TRP3TRP4, CCE1
Ensembl IDENSG00000144935ENSG00000138741ENSG00000100991
ActivatorsMetabotropic glutamate mGlu1 and orexin OX1 receptors, membrane stretch, OAG (weak and only in divalent-free extracellular solution), PLCγ stimulation, intracellular Ins(1,4,5)P3 (disputed), thapsigargin (disputed), activated by NO-mediated cysteine S-nitrosylationGq/11-coupled receptors, OAG (independent of PKC), PLCγ stimulation, Ins(1,4,5)P3 (disputed), and thapsigargin (disputed), probably activated by Ca2+ (disputed)Gq/11-coupled receptors, GTPγS (requires extracellular Ca2+), Ins(1,4,5)P3 (disputed) and thapsigargin (disputed), activated by F2v peptide and calmidazolium by antagonism of Ca2+-calmodulin, activated by NO-mediated cysteine S-nitrosylation, potentiated by extracellular protons
BlockersGd3+, La3+, 2-APB, SKF96365, Ca2+-calmodulin inhibitsGd3+, La3+, Ni2+, 2-APB, SKF96365, KB-R7943, BTP2La3+ (at mM concentrations-augments in μM range), 2-APB
Functional characteristicsγ = 16 pS (estimated by fluctuation analysis), conducts mono-and di-valent cations non-selectively; monovalent cation current suppressed by extracellular Ca2+; non-rectifying, or mildly inwardly rectifying; non-inactivating; physically associates via Homer with IP3 receptors, also associates with TRPC 3, 4 and 5, calmodulin, TRPP1, IP3 receptors, caveolin-1, enkurin and plasma membrane Ca2+-ATPase, STIM1, [see Rychkov and Barritt (2007) for additional interactions]γ = 66 pS; conducts mono-and di-valent cations non-selectively (PCa/PNa = 1.6); monovalent cation current suppressed by extracellular Ca2+; dual (inward and outward) rectification; relieved of inhibition by Ca2+-calmodulin by IP3 receptors, IP3 receptor derived peptide (F2v) and calmidazolium; inhibited by PKG-mediated phosphorylation; associates with TRPC 1, 6 and 7; also associates with IP3 receptors via Homer, ryanodine receptors, NXC1, FKBP12, syntaxin, VAMP2, caveolin-1 and calmodulinγ = 30-41 pS, conducts mono-and di-valent cations non-selectively (PCa/PNa = 1.1-7.7); dual (inward and outward) rectification; physically associates via a PDZ binding domain on NHERF with phospholipase C isoforms; also associates with TRPC1 and 5, IP3 receptors, calmodulin, STIM1, protein 4.1 and ZO-1
NomenclatureTRPC5TRPC6TRPC7
Other namesTRP5, CCE2TRP6TRP7
Ensembl IDENSG00000072315ENSG00000137672ENSG00000069018
ActivatorsGq/11-coupled receptors, Ins(1,4,5)P3, GTPγS (potentiated by extracellular Ca2+), adenophostin A and thapsigargin (disputed), La3+ (10 mM), Gd3+ (0.1 mM), elevated [Ca2+]o (5-20 mM), lysophosphatidylcholine, activated by NO-mediated cysteine S-nitrosylation, potentiated by extracellular protonsGq/11-coupled receptors, AlF4, GTPγS (but not Ins(1,4,5)P3), 20-HETE, OAG (independent of PKC) and inhibition of DAG lipase with RHC80267, synergistic stimulation by Gq/11-coupled receptors and OAG, activated by Ca2+ (disputed), AlF4, flufenamate, hyperforinGq/11-coupled receptors. OAG (independent of PKC), thapsigargin (disputed)
BlockersLa3+ (at mM concentrations-augments in μM range), 2-APB, SKF96365, KB-R7943, BTP2, flufenamic acid, chloropromazineLa3+ (IC50 ≅ 6 μM), Gd3+, amiloride,'SKF96365, 2-APB, ACA, KB-R7943, ML-9 (independent of MLCK), extracellular protonsLa3+,′SKF96365, amiloride
Functional characteristicsγ = 41-63 pS; conducts mono-and di-valent cations non-selectively (PCa/PNa = 1.8-9.5); dual rectification (inward and outward) as a homomer, outwardly rectifying when expressed with TRPC1 or TRPC4; inhibited by xestospongin C; physically associates with STIM1 and via a PDZ binding domain on NHERF with phospholipase C isoforms, in neurons associates with synaptotagmin and stathmin 2γ = 28-37 pS; conducts mono-and divalent cations with a preference for divalents (PCa/PNa = 4.5-5.0); monovalent cation current suppressed by extracellular Ca2+ and Mg2+, dual rectification (inward and outward), or inward rectification, enhanced by flufenamate; positively modulated by phosphorylation mediated by Src protein tyrosine kinases; associates with TRPC3 and 7, FKPB12, calmodulin, Fyn and MxAγ = 25-75 pS; conducts mono and divalent cations with a preference for divalents (PCa/PCs = 5.9); modest outward rectification (monovalent cation current recorded in the absence of extracellular divalents); monovalent cation current suppressed by extracellular Ca2+ and Mg2+, inhibited by intracellular Ca2+via calmodulin, associates with TRPC 1, 3 and 6, FKBP12, MxA and calmodulin

The function and regulation of heterologously expressed TRPC1 has been controversial. However, there is emerging evidence that TRPC1 is a component of a store-operated channel in situ (reviewed by Beech et al., 2005; Ambudkar et al., 2007; Worley et al., 2007). Functional hetero-oligomers of TRPC1 and TRPC4 and TRPC1 and TRPC5 activated by receptors signalling via Gq/11 have been suggested from heterologous expression systems (Strübing et al., 2001). TRPC1 may physically couple to mGlu1 and activation of the latter stimulates cation flux through TRPC1 containing-channels to produce a slow e.p.s.p. in vivo (Kim et al., 2003). Additional physiological functions involving TRPC1, including netrin-1 and BDNF-mediated growth cone guidance, are reviewed in Beech (2005) and Pedersen et al. (2005) Association of TRPC1 with the IP3 receptor via the adaptor protein, Homer, regulates channel activity (Yuan et al., 2003). For TRPC3, the stimulatory effect of Ins(1,4,5)P3 on single channel activity recorded from inside-out membrane patches is blocked by the IP3 receptor antagonists, heparin and xestospongin C. One mode of activation of TRPC3 is postulated to involve a direct association of the channel with activated IP3 receptors (reviewed by Zhu and Tang, 2004). In such a scheme, the N-terminal domain of the IP3 receptor competes with Ca2+-calmodulin (which inhibits TRPC3 activity) for a common binding site within the C-terminal domain of TRPC3 and thus relieves inhibition. A similar mechanism may apply to the gating of certain other members of the TRPC family (Tang et al., 2001). However, OAG also simulates TRPC3 channel activity independent of coupling to IP3 receptors (Ventakatchalam et al., 2001) and Src kinase appears to play an obligatory role in such activation (Vazquez et al., 2004b). Enhancement of currents mediated by TRPC3 and TRPC6 by activation of Gq/11-coupled receptors, and TRPC5 via stimulation of receptor tyrosine kinases, involves the exocytotic insertion of the channel into the plasma membrane (see Montell, 2004).

TRPM family: Members of the TRPM subfamily (reviewed by Fleig and Penner, 2004; Harteneck, 2005, Pedersen et al., 2005), on the basis of sequence homology, fall into four groups: TRPM1/3, TRPM2/8, TRPM4/5 and TRPM6/7. The properties of TRPM2 indicate that it functions as a sensor of redox status in cells (reviewed by Eisfeld and Lückhoff, 2007). TRPM3 (reviewed by Oberwinkler and Philipp, 2007) exists as multiple splice variants four of which (mTRPM3α1, mTRPM3α2, hTRPM3a and hTRPM31325) have been characterised and found to differ significantly in their biophysical properties. A splice variant of TRPM4 (i.e. TRPM4b) and TRPM5 are molecular candidates for endogenous calcium-activated cation (CAN) channels (Nilius et al., 2003; Liman, 2007; Vennekens and Nilius, 2007). TRPM4 has recent been show to be an important regulator of Ca2+ entry in to mast cells. (Vennekens et al., 2007). TRPM5 in taste receptor cells of the tongue appears essential for the transduction of sweet, amino acid and bitter stimuli (Liman, 2007). TRPM6 and 7 combine channel and enzymatic activities (‘chanzymes’) and are involved in Mg2+ homeostasis (Schmitz et al., 2003; Voets et al., 2004a; reviewed by Bodding, 2007; Penner and Fleig, 2007). TRPM8 is a channel activated by cooling and pharmacological agents evoking a ‘cool’ sensation. TRPM8(-/-) mice display pronounced deficits in the thermosensation of cold temperatures (Bautista et al., 2007; Colburn et al., 2007; Dhaka et al., 2007).

NomenclatureTRPM1TRPM2TRPM3
Other namesLTRPC1, Melastatin(TRPC7, LTRPC2)LTRPC3
Ensembl IDENSG00000134160ENSG00000142185ENSG00000083067
ActivatorsConstitutively active (disputed)Intracellular ADP ribose (ADPR) and cyclic ADPR; agents producing reactive oxygen (e.g. H2O2) and nitrogen (e.g. GEA 3162) species; potentiated by arachidonic acid and, in the presence of ADP-ribose, intracellular Ca2+via calmodulin, activated by heat ∼35°Constitutively active, current augmented by strong depolarization, stimulated by store depletion with thapsigargin, stimulated by cell swelling, activated by D-erythro-sphingosine and dihydrosphingosine
BlockersLa3+, Gd3+Clotrimazole, econazole, flufenamic acid, ACA, activation by ADPR blocked by AMP (IC50 = 70 μM)La3+, Gd3+, 2-APB, intracellar Mg2+, extracellular Na+ (TRPM3α2 only)
Functional characteristicsPermeable to Ca2+ and Ba2+; down regulated by a short splice variant of TRPM1, interacts with the short transcriptγ = 52–60 pS at negative potentials, 76 pS at positive potentials; conducts mono-and di-valent cations non-selectively (PCa/PNa = 0.6–0.7); non-rectifying; inactivation at negative potentials, activated by oxidative stress probably via PARP-1, PARP inhibitors reduce activation by oxidative stress, activation inhibited by suppression of APDR formation by glycohydrolase inhibitorsTRPM31235 γ = 83 pS (Na+ current), 65 pS (Ca2+ current); conducts mono- and di-valent cations non-selectively (PCa/PNa = 1.6); TRPM3α1; selective for monovalent cations (PCa/PCs∼0.1); TRPM3α2 conducts mono- and di-valent cations non-selectively (PCa/PCs = 1–10); outwardly rectifying (magnitude varies between spice variants).
NomenclatureTRPM4TRPM5TRPM6
Other namesLTRPC4TRP-T
Ensembl IDENSG00000130529ENSG00000070985ENSG00000119121
ActivatorsDecavanadate, whole cell current transiently activated by intracellular Ca2+ (EC50 0.3–20 μM), activated by membrane depolarization (V1/2 = −20 - + 60 mV dependent upon conditions) in the presence of elevated [Ca2+]I, heat (Q10=8.5 @ + 25 mV between 15–25 °), positively modulated by PtdIns(4,5)P2, enhanced by BTP2Gq/11-coupled receptors, Ins(1,4,5)P3, transiently activated by intracellular Ca2+ (EC50 700–840 nM), activated by membrane depolarization (V1/2 = 0 - + 120 mV dependent upon conditions), heat (Q10 = 10.3 @ - 75 mV between 15 and 25 °), stimulated by PtdIns(4,5)P2Constitutively active, activated by reduction of intracellular Mg2+, potentiated by extracellular protons, 2APB
BlockersIntracellular nucleotides (ATP4-, ADP, AMP, AMP-PNP-IC50 range 1.3-19 μM) and adenosine (IC50 630 μM); Intracellular spermine (IC50 = 35-61 μM) and flufenamic acid (IC50 = 2.8 μM), extracellular clotrimazoleIntracellular spermine (IC50 = 37 μM) and flufenamic acid (IC50 = 24 μM), extracellular protons (IC50 = 630 nM), (not inhibited by ATP4-)Ruthenium red (voltage dependent block, IC50 = 100 nM at –120 mV), inward current mediated by monovalent cations blocked by Ca2+ (IC50 = 4.8-5.4 μM) and Mg2+ (IC50 = 1.1-3.4 μM)
Functional characteristicsγ = 23 pS (within the range 60 to + 60 mV); permeable to monovalent cations; impermeable to Ca2+; strong outward rectification; slow activation at positive potentials, rapid deactivation at negative potentials, deactivation blocked by decavanadate; associates with calmodulinγ = 15-25 pS; conducts monovalent cations selectively (PCa/PNa = 0.05); strong outward rectification; slow activation at positive potentials, rapid inactivation at negative potentials; activated and subsequently desensitized by [Ca2+]I, desensitisation relieved by short chain synthetic PtdIns(4,5)P2γ = 40-87 pS; permeable to mono-and di-valent cations with a preference for divalents (Mg2+ > Ca2+; PCa/PNa = 6.9), conductance sequence Zn2+ > Ba2+ > Mg2+ = Ca2+ = Mn2+ > Sr2+ > Cd2+ > Ni2+; strong outward rectification abolished by removal of extracellular divalents, inhibited by intracellular Mg2+ (IC50 = 0.5 mM), associates with TRPM7
NomenclatureTRPM7TRPM8
Other namesTRP-PLIK, Chak1, MagNum, MICCMR1, TRP-p8
Ensembl IDENSG00000092439ENSG000000144481
ActivatorsGs-coupled receptors via elevated cAMP and activation of PKA; potentiated by intracellular ATP; positively modulated by PtdIns(4,5)P2, potentiated by extracellular protonsDepolarization (V1/2 ≅ + 50 mV at 15 °), cooling (< 22-26 °), PtdIns(4,5)P2; WS-12, icilin (requires intracellular Ca2+ as a co-factor for full agonist activity), (-)-menthol; agonist activities are temperature dependent and potentiated by cooling
BlockersSpermine (permeant blocker), La3+, Mg2+, 2-APBBCTC, capsazepine, 2-APB, La3+, ACA, anandamide, NADA, insensitive to ruthenium red
Functional characteristicsγ = 40-105 pS at negative and positive potentials respectively; conducts mono-and di-valent cations with a preference for monovalents (PCa/PNa = 0.34); conductance sequence Ni2+ > Zn2+ > Ba2+ = Mg2+ > Ca2+ = Mn2+ > Sr2+ > Cd2+, outward rectification, decreased by removal of extracellular divalent cations; inhibited by intracellular Mg2+, Ba2+, Sr +, Zn2+, Mn2+ and Mg.ATP (disputed); inhibited by Gi-coupled receptors; associates with TRPM6, snapin, Gq-PLCβ and TK(EGF)-PLCγ; kinase domain phosphorylates annexin1; activated by membrane stretch; activated by intracellular alkalinization; sensitive to osmotic gradientsγ = 40-83 pS at positive potentials; conducts mono-and di-valent cations non-selectively (PCa/PNa = 1.0-3.3); pronounced outward rectification; demonstrates densensitization to chemical agonists and adaptation to a cold stimulus in the presence of Ca2+; modulated by lysophospholipids and PUFAs

TRPM1 is decreased in melanoma cells with an inverse correlation with melanoma progression (Nilius et al., 2005a, 2007). TRPM2 possesses an ADP ribose hydrolase activity associated with a NUDT9 motif within an extended intracellular C-terminal domain of the channel (see Kühn et al., 2005). Deletion of this domain abolishes activation by H2O2. A truncated TRPM2 isoform (TRPM2-S) generated by alternative splicing prevents activation of the full-length protein (TRPM2-L) by H2O2 when co-expressed with the latter, which is important for apoptosis and cell death. TRPM4 exists as multiple splice variants: data listed are for TRPM4b. The sensitivity of TRPM4b and TRPM5 to activation by [Ca2+]i demonstrates a pronounced and time-dependent reduction following excision of inside-out membrane patches (Ullrich et al., 2005). The V1/2 for activation of TRPM4 and TRPM5 demonstrates a pronounced negative shift with increasing temperature. TRPM6 is important for Mg2+ homeostasis, mediating absorption and reabsorption of Mg2+ by the kidney intestine, respectively (Voets et al., 2004a) Loss-of-function mutations of TRPM6 result in hypomagnesaemia with secondary hypocalcaemia (HSH) (Nilius et al., 2005a, 2007). TRPM7 embodies an atypical serine/threonine protein kinase within its C-terminal domain and is subject to autophosphorylation (Runnels et al., 2001; Schmitz et al., 2003). Intact kinase activity of TRPM7 has been claimed to be required for channel function (Runnells et al., 2001) although this is disputed (Nadler et al., 2001; Schmitz et al., 2003). The kinase activity of TRPM7 modulates regulation by intracellular cAMP (Takezawa et al., 2004) but whether sensitivity to inhibition by Mg2+ is similarly affected is disputed (Schmitz et al., 2003; Matsushita et al., 2005). TRPM7 plays a major role in anoxic neuronal cell death (Aarts & Tymianski, 2005). TRPM7 present in synaptic vesicles influences neurotransmitter release from sympathetic neurones (Krapivinsky et al., 2006). Activation of TRPM8 by depolarization is strongly temperature-dependent via a channel-closing rate that decreases with decreasing temperature. The potential for half maximal depolarisation (V1/2) is shifted in the hyperpolarizing direction both by decreasing temperature and by exogenous agonists, such as menthol (Voets et al., 2004b) whereas antagonists produce depolarizing shifts in V1/2 (Mälkiä et al., 2007). The V1/2 for the native channel is far more positive than that of heterologously expressed TRPM8 (Mälkiä et al., 2007). It should be noted that menthol and structurally related compounds can elicit release of Ca2+ from the endoplasmic reticulum independent of activation of TRPM8 (Mahieu et al., 2007). Intracellular pH modulates activation of TRPM8 by cold and icilin, but not menthol (Anderson et al., 2004). TRPM8 is up-regulated in a variety of primary tumours (e.g. prostate, breast, colon, lung, skin).

TRPV family: Members of the TRPV family (reviewed by Gunthorpe et al., 2002), on the basis of structure and function, comprise four groups: TRPV1/2, TRPV3, TRPV4 and TRPV5/6. TRPV1-4 are thermosensitive, non-selective cation channels that can additionally be activated by numerous chemicals (reviewed by Benham et al., 2003, Nilius et al., 2004; Pedersen et al., 2005). Members of the TRPV family function as tetrameric complexes. Numerous splice variants of TRPV1 have been described, some of which act in a dominant negative manner when co-expressed with TRPV1 (see Pringle et al., 2007; Szallasi et al., 2007). Under physiological conditions, TRPV5 and TRPV6 are calcium selective channels involved in the absorption and reabsorption of calcium across intestinal and kidney tubule epithelia (reviewed by den Dekker et al., 2003; Nijenhuis et al., 2003).

NomenclatureTRPV1TRPV2TRPV3
Other namesVR1, vanilloid/capsaicin receptor, OTRPC1VRL-1, OTRPC2, GRC 
Ensembl IDENSG00000043316ENSG00000154039ENSG00000167723
ActivatorsDepolarization (V1/2≅0 mV at 35°), noxious heat (>43° at pH 7.4), extracellular protons (pEC50 = 5.4 at 37°), capsaicin, resiniferatoxin, vannilotoxins, phenylaceytlrivanil, olvanil, anandamide, camphor, allicin, some eicosanoids (e.g.12-(S)-HPETE, 15-(S)-HPETE, 5-(S)-HETE, leukotriene B4), NADA, 2-APB, DPBA, activated by NO-mediated cysteine S-nitrosylationNoxious heat (> 53°), probenecid, 2-APB, DPBADepolarization (V1/2 ∼ ∼ + 80mV, reduced to more negative values following heat stimuli), heat (23–39°, temperature threshold influenced by ‘thermal history’ of the cell), 6-tert-butyl-m-cresol, carvacrol, eugenol, thymol, camphor, menthol, 2-APB, DPBA, activated by NO-mediated cysteine S-nitrosylation
Blockers (IC50)Ruthenium red (0.09–0.22 μM), 5′-iodoresiniferatoxin (3.9 nM), 6-iodo-nordihydrocapsaicin (10 nM), BCTC 6–35 nM), capsazepine (40–280 nM)., A-425619 (5 nM), A-778317 (5 nM)., AMG517 (0.9 nM), AMG 628 (3.7 nM), JNJ17203212 (65 nM), JYL1421 (9.2 nM), SB366791 (18 nM), SB452533, SB-705498 (3–6 nM)Ruthenium red (0.6 μM), SKF96365, TRIM, La3+Ruthenium red (< 1μM), DPTHF (6–10 μM)
Probes (KD)[3H]-A778317 (3.4 nM), [3H]-resiniferatoxin, [125I]-resiniferatoxin  
Functional characteristicsγ = 35 pS at-60 mV; 77 pS at + 60 mV, conducts mono- and di-valent cations with a selectivity for divalents (PCa/PNa = 9.6); conducts the charged local anaesthetic QX-314; allows proton influx contributing to intracellular acidification in acidic media; voltage-and time- dependent outward rectification; potentiated by ethanol; activated/potentiated/upregulated by PKC stimulation; extracellular acidification facilitates activation by PKC; desensitisation inhibited by PKA; inhibited by PtdIns(4,5)P2 (disputed) and Ca2+/calmodulin; cooling reduces vanilloid-evoked currents; may be tonically active at body temperature; associates with TRPV3, calmodulin, PLCγTrkA, PP2B, calcineurin/cyclosporin, synaptotagmin and synapsinConducts mono- and di-valent cations (PCa/PNa = 0.9–2.9); dual (inward and outward) rectification; current increases upon repetitive activation by heat; translocates to cell surface in response to IGF-1 to induce a constitutively active conductance, translocates to the cell surface in response to membrane stretch; associates with PKA, AKAP (ACBD3), RGA (recombinase gene activator) and dystrophin-glycoprotein complexγ = 197 pS at = + 40 to + 80 mV, 48 pS at negative potentials; conducts mono-and di-valent cations; outward rectification; potentiated by arachidonic acid
NomenclatureTRPV4TRPV5TRPV6
Other namesVRL-2, OTRPC4, VR-OAC, TRP12ECaC, ECaC1, CaT2, OTRPC3ECaC2, CaT1, CaT-L
Ensembl IDENSG00000111199ENSG00000127412ENSG00000165125
ActivatorsConstitutively active, heat (> 24–32°), cell swelling (not membrane stretch or reduced internal ionic strength), responses to heat increased in hypoosmotic solutions and vice versa, bisandrographolide A, 4α-PDD, PMA, epoxyeicosatrieonic acids; sensitized by PKC, activated by NO-mediated cysteine S-nitrosylationConstitutively active (with strong buffering of intracellular Ca2+)Constitutively active (with strong buffering of intracellular Ca2+), potentiated by 2-APB
BlockersRuthenium red (voltage dependent block), La3+, Gd3+Ruthenium red (IC50 = 121 nM), econazole, miconazole, Pb2+ = Cu2+ = Gd3+ >Cd2+ >Zn2+ >La3+ >Co2+ >Fe2+; Mg2+Ruthenium red (IC50 = 9μM), Cd2+, Mg2+, La3+
Functional characteristicsγ = ∼ 60pS at −60mV, ∼90-100 pS at + 60 mV; conducts mono- and di-valent cations with a preference for divalents (PCa/PNa = 6-10); dual (inward and outward) rectification; potentiated by intracellular Ca2+via Ca2+/calmodulin; inhibited by elevated intracellular Ca2+via an unknown mechanism (IC50 = 0.4 μM); potentiated by Src family tyrosine kinase; associates with MAP7 and calmodulin, functionally associates with RyR2γ = 65-78 pS for monovalent ions at negative potentials, conducts mono-and divalents with high selectivity for divalents (PCa/PNa > 107); voltage-and time-dependent inward rectification; inhibited by intracellular Ca2+ promoting fast inactivation and slow downregulation; feedback inhibition by Ca2+ reduced by calcium binding protein 80-K-H; inhibited by extracellular acidosis; upregulated by 1,25-dihydrovitamin D3; associates with TRPV6, S100A10-annexin II, calmodulin, calbindin D28 and Rab11; activated by klotho via deglycosylationγ = 58-79 pS for monovalent ions at negative potentials, conducts mono-and divalents with high selectivity for divalents (PCa/PNa > 130); voltage-and time-dependent inward rectification; inhibited by intracellular Ca2+ promoting fast and slow inactivation; gated by voltage-dependent channel blockade by intracellular Mg2+; slow inactivation due to Ca2+-dependent calmodulin binding; phosphorylation by PKC inhibits Ca2+-calmodulin binding and slow inactivation; upregulated by 1,25-dihydroxyvitamin D3; associates with TRPV5

Activation of TRPV1 by depolarisation is strongly temperature-dependent via a channel opening rate that increases with increasing temperature. The potential for half maximal depolarisation (V1/2) is shifted in the hyperpolarizing direction both by increasing temperature and by exogenous agonists (Voets et al., 2004b). Capsaicin, resiniferatoxin and olvanil are exogenous agonists of TRPV1 that possess a vanilloid group, but the receptor is also activated by endogenous lipids that lack a vanilloid moiety (see Starowicz et al., 2007). Adenosine has been proposed to be an endogenous antagonist of TRPV1 (Puntambekar et al., 2004). TRPV2 likely plays a role in skeletal muscle and cardiac muscle degeneration and the pain pathway (Nilius et al., 2005b, 2007). The rodent, but not human, orthologues of TRPV2 are reported to be activated by heat, or 2-APB. TRPV3 can co-assemble with TRPV1 to form a functional hetero-oligomer (Smith et al., 2002). The sensitivity of TRPV4 to heat, but not 4α-PDD, is lost upon patch excision. TRPV4 is activated by anandamide and arachidonic acid following P450 epoxygenase-dependent metabolism to 5′,6′-epoxyeicosatrienoic acid (reviewed by Nilius et al., 2004). Activation of TRPV4 by cell swelling, but not heat, or phorbol esters, is mediated via the formation of epoxyeicosatrieonic acids. Phorbol esters bind directly to TRPV4. TRPV5 preferentially conducts Ca2+ under physiological conditions, but in the absence of extracellular Ca2+, conducts monovalent cations. Single channel conductances listed for TRPV5 and TRPV6 were determined in divalent cation-free extracellular solution. Ca2+-induced inactivation occurs at hyperpolarized potentials when Ca2+ is present extracellularly. Single channel events cannot be resolved (probably due to greatly reduced conductance) in the presence of extracellular divalent cations. Measurements of PCa/PNa for TRPV5 and TRPV6 are dependent upon ionic conditions due to anomalous mole fraction behaviour. Blockade of TRPV5 and TRPV6 by extracellular Mg2+ is voltage-dependent. Intracellular Mg2+ also exerts a voltage dependent block that is alleviated by hyperpolarization and contributes to the time-dependent activation and deactivation of TRPV6 mediated monovalent cation currents. TRPV5 and TRPV6 differ in their kinetics of Ca2+-dependent inactivation and recovery from inactivation. TRPV5 and TRPV6 function as homo-and hetero-tetramers. TRPV6 is up-regulated in prostate cancer. TRPV5 and TRPV6 are essential for the re-absorption and absorption of Ca2+ in the kidney and intestine, respectively.

TRPA family: The TRPA family currently comprises one mammalian member, TRPA1 (reviewed by Garcia-Anoveros and Nagata, 2007), which in some (Story et al., 2003; Bandell et al., 2004; Sawada et al., 2007), but not other (Jordt et al., 2004; Nagata et al., 2005), studies is activated by noxious cold. A recent study suggests that activation of TRPA1 is secondary to a cold-induced elevation of [Ca2+]i (Zurborg et al., 2007). Additionally, TRPA1 has been proposed to be a component of a mechanosensitive transduction channel of vertebrate hair cells (Corey et al., 2004; Nagata et al., 2005), but TRPA1(-/-) mice demonstrate no impairment in hearing, or vestibular function (Bautista et al. 2006; Kwan et al., 2006). TRPA1 acts as a nociceptor ion channel (Nagata et al., 2005; Bautista et al., 2006; Kwan et al., 2006). TRPA1 presents the unusual structural feature of 14 ankyrin repeats within the intracellular N-terminal domain.

NomenclatureTRPA1
Other namesANKTM1, p120, TRPN1
Ensembl IDENSG00000104321
ActivatorsCooling (<17 °) (disputed), (-)-menthol (1-100 μM), thymol (1-100 μM), isothiocyanates, THC, cinnamaldehyde, allicin, carvacrol, formalin, 4-hydroxy-2-nonenal, methyl-p-hydroxybenzoate, URB597, 15-deoxy-Δ(12,14)-prostaglandin J2, (insensitive to capsaicin)
BlockersRuthenium red (IC50 < 1-3 μM), menthol (1 μM), Gd3+, gentamicin, HC-030031
Functional characteristicsγ = 87-100 pS; conducts mono-and di-valent cations non-selectively (PCa/PNa = 0.84); outward rectification; inactivates in response to prolonged cooling; sensitises in response to repeated applications of cinnamaldehyde; activated by OAG and arachidonic acid downstream of receptor-mediated PLC stimulation; sensitized by PAR2 activation probably due to relief of inhibition by PtdIns(4,5)P2; activated by elevated intracellular Ca2+.

Icilin activates TRPM8 in addition to TRPA1 (Jordt et al., 2004). Activation of TRPA1 by isothiocyanates occurs via covalent modification of cysteine residues within the cytoplasmic N terminus of the channel (Hinman et al., 2006; Macpherson et al., 2007). Activation of TRPA1 by pungent chemicals has been claimed to require intracellular polyphosphates (Kim and Cavanaugh, 2007).

TRPML family: The TRPML family (see Qian and Noben-Trauth, 2005; Cantiello et al., 2005; Zeevi et al., 2007) consists of three mammalian members (TRPML1-3). TRPML channels are probably restricted to intracellular vesicles and mutations in the gene (MCOLN1) encoding TRPML1 (mucolipin-1) are the cause of the neurodegenerative disorder mucolipidosis type IV (MLIV) in man. TRPML1 is a cation selective ion channel that is important for sorting/transport of endosomes in the late endocytotic pathway and specifically fusion between late endosome-lysosome hybrid vesicles. TRPML2 (MCLN2, ENSG00000153898) and TRPML3 (ENSG00000055732) remain to be functionally characterised and are excluded from the table. TRPML3 is important for hair cell maturation, stereocilia maturation and intracellular vesicle transport.

NomenclatureTRPML1
Other namesMCLN1, mucolipin-1 (ML1)
Ensembl IDENSG00000090674
ActivatorsConstitutively active, probably activated by [Ca2+]i
BlockersAmiloride (1 mM), Gd3+, La3+, Ni2+
Functional characteristicsγ = 46pS (main state in the presence of a K+ gradient), multiple conductance states may correspond to complexes with variable channel numbers; conducts mono-and di-valent cations; channel opening decreased at negative potentials; channel opening blocked by ‘intravesicular’ acidification; loop between TM1 and TM2 is a lipase

Data in the table are for in vitro transcribed/translated TRPML1 incorporated into liposomes and studied in a lipid bilayer system (Raychowdhury et al., 2004). Mutations in TRPML3 result in the varitint waddler mouse phenotype (reviewed by Nilius et al., 2005; Qian and Noben-Trauth, 2005).

TRPP family: The TRPP family (reviewed by Delmas et al., 2004a, Delmas, 2005; Giamarchi et al., 2006; Witzgall, 2007) subsumes the polycystins that are divided into two structurally distinct groups, polycystic kidney disease 1-like (PKD1-like) and polycystic kidney disease 2-like (PKD2-like). Members of the PKD1-like group, in mammals, include PKD1 (recently reclassified as TRPP1), PDKREJ, PKD1L1, PKD1L2 and PKD1L3. The PKD2-like members comprise PKD2, PKD2L1 and PKD2L2, which have renamed TRPP2, TRPP3 and TRPP5, respectively (Moran et al., 2004). PKDREJ (ENSG00000130943), PKD1L1 (ENSG00000158683), PKD1L2 (ENSMUS00000034416), PKD1L3 (ENSG00000187008) and TRPP5 (ENSG00000078795) are not listed in the table due to lack of functional data. Similarly, TRPP1 (ENSG00000008710) is also omitted because although one study (Babich et al., 2004) has reported the induction of a cation conductance in CHO cells transfected with TRPP1, there is no unequivocal evidence that TRPP1 is a channel per se and in other studies (e.g. Hanaoka et al., 2000; Delmas et al., 2004b) TRPP1 is incapable of producing currents. Conversely, TRPP1 has been demonstrated to constitutively activate G-proteins and subsequently c-Jun N-terminal kinase. Unlike other TRP channels, TRPP1 contains 11 putative transmembrane domains and an extremely large and complex extracellular N-terminal domain that contains several adhesive domains. There is good evidence that TRPP1 and TRPP2 physically couple to act as a signalling complex (Delmas, 2004a). The association of TRPP1 and TRPP2 suppresses the G-protein stimulating activity of TRPP1 and also the constitutive channel activity of TRPP2. Antibodies directed against the REJ domain of TRPP1 alleviate such mutual inhibition, simultaneously enhancing TRPP2 channel gating and the activation of G-proteins by TRPP1.

NomenclatureTRPP2TRPP3
Other namesPolycystin-2 (PC2), polycystic kidney disease 2 (PKD2)Polycystic kidney disease 2-like 1 protein (PKD2L1)
Ensembl IDENSG00000118762ENSG00000107593
ActivatorsConstitutive activity, suppressed by co-expression of TRPP1Low constitutive activity, enhanced by intracellular Ca2+
Blockers (IC50)La3+, Gd3+, amiloridePhenamil (0.14 μM), benzamil (1.1 μM), EIPA (10.5 μM), amiloride (143 μM), La3+, Gd3+, flufenamate
Functional characteristicsγ = 123-177 pS (with K+ as charge carrier); PNa/PK = 0.14-1.1; conducts both mono-and di-valent cations; probably associates with TRPV4; also associates with cortactin and cadherin via TRPP1; channel activity increased by association with α-actinin; interacts with several cytoskeletal proteins that determine subcellular distribution including CD2AP, AP-1, PACS-1 and 2, COPI and PIGEA-14γ = 137 pS (outward conductance) 399 pS (inward conductance), conducts mono-and di-valent cations with a preference for divalents (PCa/PNa = 4.3); slight inward rectification; activated and subsequently inactivated by intracellular Ca2+; inhibited by extracellular acidosis; possibly interacts with TRPA1

Data in the table are extracted from Delmas et al. (2004a) and Dai et al. (2007). Broadly similar single channel conductance, mono-and di-valent cation selectivity and sensitivity to blockers are observed for TRPP2 co-expressed with TRPP1 (Delmas, 2004b). TRPP2 is important for cilia movement, development of the heart, skeletal muscle and kidney. TRPP2 is also likely to act as an intracellular Ca2+-release channel. Ca2+, Ba2+ and Sr2+ permeate TRPP3, but reduce inward currents carried by Na+. Mg2+ is largely impermeant and exerts a voltage dependent inhibition that increases with hyperpolarization. TRPP3 plays a role in retinal development.

Abbreviations: 2-APB, 2-amino ethoxyphenylborate; 4α-PDD, 4α-phorbol 12, 13-didecanoate; 5-(S)-HETE, 5-(S)-hydroxyeicosatetraenoic acid; 12-(S)-HPETE and 15-(S)-HPETE, 12- and 15-(S)-hydroperoxyeicosatetraenoic acids; 20-HETE, 20-hydroxyeicosatetraenoic acid; A-425619, 1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)urea; A-778317, 1-((R)-5-tert-butyl-indan-1-yl)-3-isoquinolin-5-yl-urea; ACA,N-(p-amylcinnamoyl)anthranilic acid; AMG 517,N-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide; AMG628, (R)-N-(4-(6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide; BCTC,N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide; BTP2, 4-methy-4′-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]-1,2,3-thiadiazole-5-carboxanilide; DPBA, diphenylboronic anhydride; DPTHF, diphenyltetrahydrofuran; GEA3162, 1,2,3,4-oxatriazolium-5-amino-3-(3,4-dichlorophenyl)-chloride; JYL1421,N-(4-tert-butylbenzyl)-N'-[3-fluoro-4-(methylsulfonylamino)benzyl]thiourea; JNJ17203212, 4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid (5-trifluoromethyl-pyridin-2-yl)-amide; KB-R7943, 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulfonate; OAG, 1-oleoyl-2-acetyl-sn-glycerol; ML-9, 1-(5-chloronaphtalene-1-sulphonyl)homopiperazine; NADA,N-arachidonyl dopamine; PMA, phorbol 12 myristate 13-acetate; RHC80267, 1,6-di[O-(carbamoyl)cyclohexanone oxime]hexane; SB366791,N-(3-methoxyphenyl)-4-chlorocinnamide; SB705498,N-(2-bromophenyl)-N'-[((R)-1-(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea; SDZ249665, 1-[4-(2-amino-ethoxy)-3-methoxy-benzyl]-3-(4-tert-butyl-benzyl)-urea; SKF96265, 1-(β-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenethyl)-1H-imidazole hydrochloride; THC, Δ9-tetrahydrocannabinol; TRIM, 1-(2-(trifluoromethyl)phenyl) imidazole; URB597, 3′-carbamoylbiphenyl-3-yl cyclohexylcarbamate; WS-12, 2-isopropyl-5-methyl-cyclohexanecarboxylic acid (4-methoxy-phenyl)-amide

Further Reading

Aarts MM, Tymianski M (2005). TRPM7 and ischemic brain injury. Neuroscientist11: 116–123.

Ambudkar IS, Ong HL, Liu X, Bandyopadhyay B, Cheng KT (2007). TRPC1: the link between functionally distinct store-operated calcium channels. Cell Calcium42: 213–223.

Beech DJ (2005). TRPC1: store-operated channel and more. Pflügers Arch451: 53–60.

Beech DJ, Muraki K, Flemming R (2004). Non-selective cationic channels of smooth muscle and the mammalian homologues of Drosophila TRP. J Physiol559: 685–706.

Benham CD, Gunthorpe MJ, Davis JB (2003). TRPV channels as temperature sensors. Cell Calcium33: 479–487.

Bodding M (2007). TRPM6: A Janus-like protein. Handb Exp Pharmacol179: 299–311.

Cantiello HF, Montalbetti N, Goldman WH, Raychowdhury MK, González-Perrett S, Timpanaro GA et al. (2005). Cation channel activity of mucolipin-1: the effect of calcium. Pflügers Arch451: 304–312.

Caterina MJ, Julius D (2001). The vanilloid receptor: a molecular gateway to the pain pathway. Annu Rev Neurosci24: 487–517.

Clapham DE (2003). TRP channels as cellular sensors. Nature426: 517–524.

Clapham DE, Montell C, Schultz G, Julius D (2003). International Union of Pharmacology. XLIII. Compendium of Voltage-gated ion channels. Transient receptor potential channels. Pharmacol Rev55: 591–596.

Delmas P (2005). Polycystins: polymodal receptor/ion-channel cellular sensors. Pflügers Arch451: 264–276.

Delmas P, Padilla F, Osorio N, Coste B, Raoux M, Crest M (2004a). Polycystins, calcium signaling, and human diseases. Biochem Biophys Res Commun322: 1374–1383.

Den Dekker E, Hoenderop JG, Nilius B, Bindels RJ (2003). The epithelial calcium channels, TRPV5 & TRPV6: from identification towards regulation. Cell Calcium33: 497–507.

Dhaka A, Viswanath V, Patapoutian A (2006). Trp ion channels and temperature sensation. Annu Rev Neurosci29: 135–161.

Eisfeld A, Lückhoff J (2007). TRPM2. Handb Exp Pharmacol179: 237–252.

Fleig A, Penner R (2004). The TRPM ion channel subfamily: molecular, biophysical and functional features. Trends Pharmacol Sci25: 633–639.

Freichel M, Vennekens R, Olausson J, Stolz S, Philipp SE, Weißgerber P et al. (2005). Functional role of TRPC proteins in native systems: implications from knockout and knock-down studies. J Physiol567: 59–66.

Garcia-Anoveros J, Nagata K (2007). TRPA1. Handb Exp Pharmacol179: 347–362.

Giamarchi A, Padilla F, Coste B, Raoux M, Crest M, Honore E et al. (2006). The versatile nature of the calcium-permeable cation channel TRPP2. EMBO Rep7: 787–793.

Gunthorpe MJ, Benham CD, Randall A, Davis JD (2002). The diversity in the vanilloid (TRPV) receptor family of ion channels. Trends Pharmacol Sci23: 183–191.

Harteneck C (2005). Function and Pharmacology of TRPM cations channels. Naunyn-Schmiedeberg's Arch Pharmacol371: 307–314.

Jordt SE, McKemy DD, Julius D (2003). Lessons from peppers and peppermint: the molecular logic of thermosensation. Curr Opin Neurobiol13: 487–492.

Kiselyov K, Shin DM, Kim JY, Yuan JP, Muallem S (2007b). TRPC channels: interacting proteins. Handb Exp Pharmacol179: 559–574.

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Liman ER (2007). TRPM5 and taste transduction. Handb Exp Pharmacol179: 287–298.

Macpherson LJ, Hwang SW, Miyamoto T, Dubin AE, Patapoutian A, Story GM (2006). More than cool: promiscuous relationships of menthol and other sensory compounds. Mol Cell Neurosci32: 335–343.

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Montell C (2005). The TRP superfamily of cation channels. Science STKE272: re3.

Moran MM, Xu H, Clapham DE (2004). TRP ion channels in the nervous system. Curr Opin Neurobiol14: 362–369.

Nijenhuis T, Hoenderop JG, Nilius B, Bindels RJ (2003). (Patho)physiological implications of the novel epithelial Ca2+ channels TRPV5 and TRPV6. Pflügers Arch446: 401–409.

Nilius B (2003a). From TRPs to SOCs, CCEs, and CRACs: consensus and controversies. Cell Calcium33: 293–298.

Nilius B (2003b). Calcium-impermeable monovalent cation channels: a TRP connection? Br J Pharmacol138: 5–7.

Nilius B, Droogmans G, Wondergem R (2003). Transient receptor potential channels in endothelium: solving the calcium entry puzzle? Endothelium10: 5–15.

Nilius B, Vriens J, Prenen J, Droogmans G, Voets T (2004). TRPV4 calcium channel: a paradigm for gating diversity. Am J Physiol286: C195–C205.

Nilius B, Owsianik G, Voets T, Peters JA (2007). Transient receptor potential (TRP) cation channels in disease. Physiol Rev87: 165–217.

Nilius B, Talavera K, Owsianik G, Prenen J, Droogmans G, Voets T (2005b). Gating of TRP channels: a voltage connection? J Physiol567: 35–44.

Nilius B, Voets T (2005). A TR(I)P through a world of multifunctional cation channels. Pflügers Arch451: 1–10.

Nilius B, Voets T, Peters J (2005a). TRP Channels in disease. Sci STKE295: re8.

Owsianik G, D'hoedt D, Voets T, Nilius B (2006a). Structure-function relationship of the TRP channel superfamily. Rev Physiol Biochem Pharmacol156: 61–90.

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Plant TD, Schaefer M (2003). TRPC4 and TRPC5: receptor-operated Ca2+-permeable non-selective cation channels. Cell Calcium33: 441–450.

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Voets T, Owsainik G, Nilius B (2007). TRPM8. Handb Exp Pharmacol179: 329–344.

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Citation Information

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

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

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