The Concise Guide to PHARMACOLOGY 2015/16: Voltage‐gated ion channels

1The authors state that there are no conflicts of interest to declare.

25905 CatSper and Two‐Pore channels

35907 Cyclic nucleotide‐regulated channels

45909 Potassium channels

55910 Calcium‐activated potassium channels

65912 Inwardly rectifying potassium channels

75915 Two‐P potassium channels

85917 Voltage‐gated potassium channels

95920 Transient Receptor Potential channels

105934 Voltage‐gated calcium channels

115936 Voltage‐gated proton channel

125937 Voltage‐gated sodium channels

13CatSper channels (CatSper1‐4, nomenclature as agreed by NC‐IUPHAR[64]) 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[171]. In mammals, CatSper subunits are structurally most closely related to individual domains of voltage‐activated calcium channels (Cav) [308]. CatSper1 [308], CatSper2 [302] and CatSpers 3 and 4 [155, 221, 299], in common with a putative 2TM auxiliary CatSperβ protein [218] and two putative 1TM associated CatSperγ and CatSperδ proteins [59, 382], are restricted to the testis and localised to the principle piece of sperm tail.

14Two‐pore channels (TPCs) are structurally related to CatSpers, CaVs and NaVs. TPCs have a 2x6TM structure with twice the number of TMs of CatSpers and half that of CaVs. There are three animal TPCs (TPC1‐TPC3). Humans have TPC1 and TPC2, but not TPC3. TPC1 and TPC2 are localized in endosomes and lysosomes [39]. TPC3 is also found on the plasma membrane and forms a voltage‐activated, non‐inactivating Na+ channel [40]. All the three TPCs are Na+‐selective under whole‐cell or whole‐organelle patch clamp recording [41, 42, 404]. The channels may also conduct Ca2+[243].

15CatSper channel subunits expressed singly, or in combination, fail to functionally express in heterologous expression systems [302, 308]. 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 andCatsper1 (−/−) mice [171] and also mature human sperm [215, 343]. ICatSper is also undetectable in the spermatozoa of Catsper2 (−/−),Catsper3 (−/−), Catsper4 (−/−), or CatSperδ (−/−) mice, and CatSper 1 associates with CatSper 2, 3, 4, β, γ, and δ[59, 218, 299]. Moreover, targeted disruption of Catsper1, 2, 3, 4, or δ 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 [47, 59, 299]. Thus, it is likely that the CatSper pore is formed by a heterotetramer of CatSpers1‐4 [299] in association with the auxiliary subunits (β, γ, δ) that are also essential for function [59]. CatSper channels are required for the increase in intracellular Ca2+ concentration in sperm evoked by egg zona pellucida glycoproteins [404]. Mouse and human sperm swim against the fluid flow and Ca2+ signaling through CatSper is required for the rheotaxis [239]. In vivo, CatSper1‐null spermatozoa cannot ascend the female reproductive tracts efficiently [60, 135]. It has been shown that CatSper channels form four linear Ca2+ signaling domains along the flagella, which orchestrate capacitation‐associated tyrosine phosphorylation [60].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 [253]. Mouse KSper is encoded by mSlo3, a protein detected only in testis [235, 253, 419]. In human sperm, such alkalinization may result from the activation of Hv1, a proton channel [216].

16Mutations in CatSpers are associated with syndromic and non‐syndromic male infertility [128]. In human ejaculated spermatozoa, progesterone (<50 nM) potentiates the CatSper current by a non‐genomic mechanism and acts synergistically with intracellular alkalinisation [215, 343]. Sperm cells from infertile patients with a deletion in CatSper2 gene lack ICatSper and the progesterone response [331]. In addition, certain prostaglandins (e.g. PGF1α, PGE1) also potentiate CatSper mediated currents [215, 343].

17In human sperm, CatSper channels are also activated by various small molecules including endocrine disrupting chemicals (EDC) and proposed as a polymodal sensor [35, 35].

18TPCs are the major Na+ conductance in lysosomes; knocking out TPC1 and TPC2 eliminates the Na+ conductance and renders the organelle's membrane potential insensitive to changes in [Na+] (31). The channels are regulated by luminal pH [41], PI(3,5)P2[387], intracellular ATP and extracellular amino acids [42]. TPCs are also involved in the NAADP‐activated Ca2+ release from lysosomal Ca2+ stores [39, 243]. Mice lacking TPCs are viable but have phenotypes including compromised lysosomal pH stability, reduced physical endurance [42], resistance to Ebola viral infection [314] and fatty liver [110]. No major human disease‐associated TPC mutation has been reported.

19Calcraft PJ et al. (2009) NAADP mobilizes calcium from acidic organelles through two‐pore channels. Nature 459: 596‐600 [PMID:19387438]

20Cang C et al. (2014) The voltage‐gated sodium channel TPC1 confers endolysosomal excitability. Nat. Chem. Biol. 10: 463‐9 [PMID:24776928]

21Cang C et al. (2013) mTOR regulates lysosomal ATP‐sensitive two‐pore Na(+) channels to adapt to metabolic state. Cell 152: 778‐90 [PMID:23394946]

22Clapham DE et al. (2005) International Union of Pharmacology. L. Nomenclature and structure‐function relationships of CatSper and two‐pore channels. Pharmacol. Rev. 57: 451‐4 [PMID:16382101]

23Hildebrand MS et al. (2010) Genetic male infertility and mutation of CATSPER ion channels. Eur. J. Hum. Genet. 18: 1178‐84 [PMID:20648059]

24Kirichok Y et al. (2011) Rediscovering sperm ion channels with the patch‐clamp technique. Mol. Hum. Reprod. 17: 478‐99 [PMID:21642646]

25Lishko PV et al. (2010) The role of Hv1 and CatSper channels in sperm activation. J. Physiol. (Lond.) 588: 4667‐72 [PMID:20679352]

26Ren D et al. (2010) Calcium signaling through CatSper channels in mammalian fertilization. Physiology (Bethesda) 25: 165‐75 [PMID:20551230]

27Wang X et al. (2012) TPC proteins are phosphoinositide‐ activated sodium‐selective ion channels in endosomes and lysosomes. Cell 151: 372‐83 [PMID:23063126]

28Cyclic 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 [138].

29CNG 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 [96, 166], where light signals through rhodopsin and transducin to stimulate phosphodiesterase and reduce intracellular cyclic GMP level. This results in a closure of CNG channels and a reduced ‘dark current’. Similar channels were found in the cilia of olfactory neurons [252] and the pineal gland [86]. 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.

30CNGA1, CNGA2 and CNGA3 express functional channels as homomers. Three additional subunits CNGA4 (Q8IV77), CNGB1 (Q14028) and CNGB3(Q9NQW8) 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 [287, 393, 420, 421, 423].

31The hyperpolarisation‐activated, cyclic nucleotide‐gated (HCN) channels are cation channels that are activated by hyperpolarisation at voltages negative to ‐50 mV. The cyclic nucleotides cyclic AMP and cyclic GMP 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 [82, 274]. In native cells, these currents have a variety of names, such as I h, I q andI f. 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 [7]. A standardised nomenclature for HCN channels has been proposed by the NC‐IUPHAR subcommittee on voltage‐gated ion channels [138].

32HCN 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 [32] and ivabradine [38] have proven useful in identifying and studying functional HCN channels in native cells. Zatebradine and cilobradine are also useful blocking agents.

33Baruscotti M et al. (2010) HCN‐related channelopathies. Pflugers Arch. 460: 405‐15 [PMID:20213494]

34Baruscotti M et al. (2005) Physiology and pharmacology of the cardiac pacemaker ("funny") current. Pharmacol. Ther. 107: 59‐79 [PMID:15963351]

35Biel M et al. (2009) Cyclic nucleotide‐gated channels. Handb Exp Pharmacol 111‐36 [PMID:19089328]

36Biel M et al. (2009) Hyperpolarization‐activated cation channels: from genes to function. Physiol. Rev. 89: 847‐85 [PMID:19584315]

37Bois P et al. (2007) Molecular regulation and pharmacology of pacemaker channels. Curr. Pharm. Des. 13: 2338‐49 [PMID:17692005]

38Bradley J et al. (2005) Regulation of cyclic nucleotide‐gated channels. Curr. Opin. Neurobiol. 15: 343‐9 [PMID:15922582]

39Brown RL et al. (2006) The pharmacology of cyclic nucleotide‐gated channels: emerging from the darkness. Curr. Pharm. Des. 12: 3597‐613 [PMID:17073662]

40Craven KB et al. (2006) CNG and HCN channels: two peas, one pod. Annu. Rev. Physiol. 68: 375‐401 [PMID:16460277]

41Cukkemane A et al. (2011) Cooperative and uncooperative cyclic‐nucleotide‐gated ion channels. Trends Biochem. Sci. 36: 55‐64 [PMID:20729090]

42DiFrancesco D. (2010) The role of the funny current in pacemaker activity. Circ. Res. 106: 434‐46 [PMID:20167941]

43Dunlop J et al. (2009) Hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels and pain. Curr. Pharm. Des. 15: 1767‐72 [PMID:19442189]

44Hofmann F et al. (2005) International Union of Pharmacology. LI. Nomenclature and structure‐function relationships of cyclic nucleotide‐regulated channels. Pharmacol. Rev. 57: 455‐62 [PMID:16382102]

45Maher MP et al. (2009) HCN channels as targets for drug discovery. Comb. Chem. High Throughput Screen. 12: 64‐72 [PMID:19149492]

46Mazzolini M et al. (2010) Gating in CNGA1 channels. Pflugers Arch. 459: 547‐55 [PMID:19898862]

47Meldrum BS et al. (2007) Molecular targets for antiepileptic drug development. Neurotherapeutics 4: 18‐61 [PMID:17199015]

48Tardif JC. (2008) Ivabradine: I(f) inhibition in the management of stable angina pectoris and other cardiovascular diseases. Drugs Today 44: 171‐81 [PMID:18536779]

49Wahl‐Schott C et al. (2009) HCN channels: structure, cellular regulation and physiological function. Cell. Mol. Life Sci. 66: 470‐94 [PMID:18953682]

50Potassium 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 a subunit often associated with auxiliary regulatory subunits. Since there are over 70 different genes encoding K channels α subunits 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. 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 [106, 120, 191, 392].

51Ahern CA et al. (2009) Chemical tools for K(+) channel biology. Biochemistry 48: 517‐26 [PMID:19113860]

52Bayliss DA et al. (2008) Emerging roles for two‐pore‐domain potassium channels and their potential therapeutic impact. Trends Pharmacol. Sci. 29: 566‐75 [PMID:18823665]

53Bean BP. (2007) The action potential in mammalian central neurons. Nat. Rev. Neurosci. 8: 451‐65 [PMID:17514198]

54Dalby‐Brown W et al. (2006) K(v)7 channels: function, pharmacology and channel modulators. Curr Top Med Chem 6: 999‐1023 [PMID:16787276]

55Enyedi P et al. (2010) Molecular background of leak K+ currents: two‐pore domain potassium channels. Physiol. Rev. 90: 559‐605 [PMID:20393194]

56Goldstein SA et al. (2005) International Union of Pharmacology. LV. Nomenclature and molecular relationships of two‐P potassium channels. Pharmacol. Rev. 57: 527‐40 [PMID:16382106]

57Gutman GA et al. (2005) International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage‐gated potassium channels. Pharmacol. Rev. 57: 473‐508 [PMID:16382104]

58Hancox JC et al. (2008) The hERG potassium channel and hERG screening for drug‐induced torsades de pointes. Pharmacol. Ther. 119: 118‐32 [PMID:18616963]

59Hansen JB. (2006) Towards selective Kir6.2/SUR1 potassium channel openers, medicinal chemistry and therapeutic perspectives. Curr. Med. Chem. 13: 361‐76 [PMID:16475928]

60Honoré E. (2007) The neuronal background K2P channels: focus on TREK1. Nat. Rev. Neurosci. 8: 251‐61 [PMID:17375039]

61Jenkinson DH. (2006) Potassium channels–multiplicity and challenges. Br. J. Pharmacol. 147 Suppl 1: S63‐71 [PMID:16402122]

62Judge SI et al. (2006) Potassium channel blockers in multiple sclerosis: neuronal Kv channels and effects of symptomatic treatment. Pharmacol. Ther. 111: 224‐59 [PMID:16472864]

63Kannankeril P et al. (2010) Drug‐induced long QT syndrome. Pharmacol. Rev. 62: 760‐81 [PMID:21079043]

64Kobayashi T et al. (2006) G protein‐activated inwardly rectifying potassium channels as potential therapeutic targets. Curr. Pharm. Des. 12: 4513‐23 [PMID:17168757]

65Kubo Y et al. (2005) International Union of Pharmacology. LIV. Nomenclature and molecular relationships of inwardly rectifying potassium channels. Pharmacol. Rev. 57: 509‐26 [PMID:16382105]

66Lawson K et al. (2006) Modulation of potassium channels as a therapeutic approach. Curr. Pharm. Des. 12: 459‐70 [PMID:16472139]

67Mannhold R. (2006) Structure‐activity relationships of K(ATP) channel openers. Curr Top Med Chem 6: 1031‐47 [PMID:16787278]

68Mathie A et al. (2007) Therapeutic potential of neuronal two‐pore domain potassium‐channel modulators. Curr Opin Investig Drugs 8: 555‐62 [PMID:17659475]

69Nardi A et al. (2008) BK channel modulators: a comprehensive overview. Curr. Med. Chem. 15: 1126‐46 [PMID:18473808]

70Pongs O et al. (2010) Ancillary subunits associated with voltage‐dependent K+ channels. Physiol. Rev. 90: 755‐96 [PMID:20393197]

71Salkoff L et al. (2006) High‐conductance potassium channels of the SLO family. Nat. Rev. Neurosci. 7: 921‐31 [PMID:17115074]

72Stocker M. (2004) Ca(2+)‐activated K+ channels: molecular determinants and function of the SK family. Nat. Rev. Neurosci. 5: 758‐70 [PMID:15378036]

73Takeda M et al. (2011) Potassium channels as a potential therapeutic target for trigeminal neuropathic and inflammatory pain. Mol Pain 7: 5 [PMID:21219657]

74Trimmer JS et al. (2004) Localization of voltage‐gated ion channels in mammalian brain. Annu. Rev. Physiol. 66: 477‐519 [PMID:14977411]

75Wang H et al. (2007) ATP‐sensitive potassium channel openers and 2,3‐dimethyl‐2‐butylamine derivatives. Curr. Med. Chem. 14: 133‐55 [PMID:17266574]

76Weatherall KL et al. (2010) Small conductance calcium‐activated potassium channels: from structure to function. Prog. Neurobiol. 91: 242‐55 [PMID:20359520]

77Wei AD et al. (2005) International Union of Pharmacology. LII. Nomenclature and molecular relationships of calcium‐activated potassium channels. Pharmacol. Rev. 57: 463‐72 [PMID:16382103]

78Wickenden AD et al. (2009) Kv7 channels as targets for the treatment of pain. Curr. Pharm. Des. 15: 1773‐98 [PMID:19442190]

79Witchel HJ. (2007) The hERG potassium channel as a therapeutic target. Expert Opin. Ther. Targets 11: 321‐36 [PMID:17298291]

80Wulff H et al. (2009) Voltage‐gated potassium channels as therapeutic targets. Nat Rev Drug Discov 8: 982‐1001 [PMID:19949402]

81The 6TM family of K channels comprises the voltage‐gated KVsubfamilies, the KCNQ subfamily, the EAG subfamily (which includes herg channels), the Ca2+‐activated Slo subfamily (actually with 6 or 7TM) and the Ca2+‐activated SK subfamily. As for the 2TM family, the pore‐forming a subunits form tetramers and heteromeric channels may be formed within subfamilies (e.g. KV1.1 with KV1.2; KCNQ2 with KCNQ3).

82The 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 a subunits form tetramers, and heteromeric channels may be formed within subfamilies (e.g. Kir3.2 with Kir3.3).

83The 4TM family of K channels are thought to underlie many background K 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 K2P9.1). There is no current, clear, consensus on nomenclature of 4TM K channels, nor on the division into subfamilies [106]. The suggested division into subfamilies, below, is based on similarities in both structural and functional properties within subfamilies.

84The 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 tetraethylammonium and fampridine, but are blocked to varying degrees by Ba2+ ions.

85The 6TM family of K channels comprises the voltage‐gated KVsubfamilies, the KCNQ subfamily, the EAG subfamily (which includes herg channels), the Ca2+‐activated Slo subfamily (actually with 6 or 7TM) and the Ca2+‐activated SK subfamily. As for the 2TM family, the pore‐forming a subunits form tetramers and heteromeric channels may be formed within subfamilies (e.g. KV1.1 with KV1.2; KCNQ2 with KCNQ3).

86The TRP superfamily of channels (nomenclature as agreed by NC‐IUPHAR[65, 402]), whose founder member is the Drosophila Trp channel, exists in mammals as six families; TRPC, TRPM, TRPV, TRPA, TRPP and TRPML based on amino acid homologies. TRP subunits contain six putative transmembrane domains and assemble as homo‐ or hetero‐tetramers to form cation selective channels with diverse modes of activation and varied permeation properties (reviewed by [273]). Established, or potential, physiological functions of the individual members of the TRP families are discussed in detail in the recommended reviews and a compilation edited by Islam [151]. The established, or potential, involvement of TRP channels in disease is reviewed in [174, 258] and [260], together with a special edition of Biochemica et Biophysica Acta on the subject [258]. The pharmacology of most TRP channels is poorly developed [402]. Broad spectrum agents are listed in the tables along with more selective, or recently recognised, ligands that are flagged by the inclusion of a primary reference. Most TRP channels are regulated by phosphoinostides such as PtIns(4,5)P2and IP3 although the effects reported are often complex, occasionally contradictory, and likely to be dependent upon experimental conditions, such as intracellular ATP levels (reviewed by [261, 310, 372]). Such regulation is generally not included in the tables. When thermosensitivity is mentioned, it refers specifically to a high Q10 of gating, often in the range of 10‐30, but does not necessarily imply that the channel's function is to act as a 'hot' or 'cold' sensor. In general, the search for TRP activators has led to many claims for temperature sensing, mechanosensation, and lipid sensing. All proteins are of course sensitive to energies of binding, mechanical force, and temperature, but the issue is whether the proposed input is within a physiologically relevant range resulting in a response.

87TRPA1 is the sole mammalian member of this group (reviewed by [101]). TRPA1 activation of sensory neurons contribute to nociception [158, 238, 339]. Pungent chemicals such as mustard oil (AITC), allicin, and cinnamaldehyde activate TRPA1 by modification of free thiol groups of cysteine side chains, especially those located in its amino terminus [21, 133, 226, 228]. Alkenals with α, β‐unsaturated bonds, such as propenal (acrolein), butenal (crotylaldehyde), and 2‐pentenal can react with free thiols via Michael addition and can activate TRPA1. However, potency appears to weaken as carbon chain length increases [12, 21]. Covalent modification leads to sustained activation of TRPA1. Chemicals including carvacrol, menthol, and local anesthetics reversibly activate TRPA1 by non‐covalent binding [164, 201, 407, 408]. TRPA1 is not mechanosensitive under physiological conditions, but can be activated by cold temperatures [165, 429]. The electron cryo‐EM structure of TRPA1 [279] indicates that it is a 6‐TM homotetramer. Each subunit of the channel contains two short ‘pore helices’ pointing into the ion selectivity filter, which is big enough to allow permeation of partially hydrated Ca2+ ions. A coiled‐coil domain in the carboxy‐terminal region forms the cytoplasmic stalk of the channel, and is surrounded by 16 ankyrin repeat domains, which are speculated to interdigitate with an overlying helix‐turn‐helix and putative β‐sheet domain containing cysteine residues targeted by electrophilic TRPA1 agonists. The TRP domain, a helix at the base of S6, runs perpendicular to the pore helices suspended above the ankyrin repeats below, where it may contribute to regulation of the lower pore. The coiled‐coil stalk mediates bundling of the four subunits through interactions between predicted α‐helices at the base of the channel.

88Members of the TRPC subfamily (reviewed by [2, 8, 25, 29, 99, 172, 278, 298]) fall into the subgroups outlined below. TRPC2 (not tabulated) is a pseudogene in man. It is generally accepted that all TRPC channels are activated downstream of Gq/11‐coupled receptors, or receptor tyrosine kinases (reviewed by [294, 364, 402]). A comprehensive listing of G‐protein coupled receptors that activate TRPC channels is given in [2]. Hetero‐oligomeric complexes of TRPC channels and their association with proteins to form signalling complexes are detailed in [8] and [173]. TRPC channels have frequently been proposed to act as store‐operated channels (SOCs) (or compenents of mulimeric complexes that form SOCs), activated by depletion of intracellular calcium stores (reviewed by [8, 56, 285, 295, 315, 416]), However, the weight of the evidence is that they are not directly gated by conventional store‐operated mechanisms, as established for Stim‐gated Orai channels. TRPC channels are not mechanically gated in physiologically relevant ranges of force. All members of the TRPC family are blocked by 2‐APB and SKF96365[124, 125]. Activation of TRPC channels by lipids is discussed by [25].

89TRPC4/C5 may be distinguished from other TRP channels by their potentiation by micromolar concentrations of La3+.

90All members are activated by diacylglycerol independent of protein kinase C stimulation [125].

91Members of the TRPM subfamily (reviewed by [97, 124, 285, 422]) fall into the five subgroups outlined below.

92TRPM1 exists as five splice variants and is involved in normal melanocyte pigmentation [268] and is also a visual transduction channel in retinal ON bipolar cells [183]. TRPM3 (reviewed by [270]) 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. TRPM3 may contribute to the detection of noxious heat [376].

93TRPM2 is activated under conditions of oxidative stress (reviewed by [412]). Numerous splice variants of TRPM2 exist which differ in their activation mechanisms [87]. The C‐terminal domain contains a TRP motif, a coiled‐coil region, and an enzymatic NUDT9 homologous domain. TRPM2 appears not to be activated by NAD, NAAD, or NAADP, but is directly activated by ADPRP (adenosine‐5'‐O‐disphosphoribose phosphate) [365].

94TRPM4 and TRPM5 have the distinction within all TRP channels of being impermeable to Ca2+[402]. A splice variant of TRPM4 (i.e.TRPM4b) and TRPM5 are molecular candidates for endogenous calcium‐activated cation (CAN) channels [115]. TRPM4 has been shown to be an important regulator of Ca2+ entry in to mast cells [368] and dendritic cell migration [18]. TRPM5 in taste receptor cells of the tongue appears essential for the transduction of sweet, amino acid and bitter stimuli [212].

95TRPM6 and 7 combine channel and enzymatic activities (‘chanzymes’). These channels have the unusual property of permeation by divalent (Ca2+, Mg2+, Zn2+) and monovalent cations, high single channel conductances, but overall extremely small inward conductance when expressed to the plasma membrane. They are inhibited by internal Mg2+ at 0.6 mM, around the free level of Mg2+ in cells. Whether they contribute to Mg2+ homeostasis is a contentious issue. When either gene is deleted in mice, the result is embryonic lethality. The C‐terminal kinase region is cleaved under unknown stimuli, and the kinase phosphorylates nuclear histones.

96Is a channel activated by cooling and pharmacological agents evoking a ‘cool’ sensation and participates in the thermosensation of cold temperatures [23, 66, 81] reviewed by [179, 220, 248, 373].

97The TRPML family [297, 300, 417] 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 one 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. TRPML3 is important for hair cell maturation, stereocilia maturation and intracellular vesicle transport. A naturally occurring gain of function mutation in TRPML3 (i.e. A419P) results in the varitint waddler (Va) mouse phenotype (reviewed by [262, 300]).

98The TRPP family (reviewed by [78, 80, 104, 137, 399]) or PKD2 family is comprised of PKD2, PKD2L1 and PKD2L2, which have been renamed TRPP1, TRPP2 and TRPP3, respectively [402]. They are clearly distinct from the PKD1 family, whose function is unknown. Although still being sorted out, TRPP family members appear to be 6TM spanning nonselective cation channels.

99Members of the TRPV family (reviewed by [369]) can broadly be divided into the non‐selective cation channels, TRPV1‐4 and the more calcium selective channels TRPV5 and TRPV6.

100TRPV1 is involved in the development of thermal hyperalgesia following inflammation and may contribute to the detection of noxius heat (reviewed by [293, 335, 347]). Numerous splice variants of TRPV1 have been described, some of which modulate the activity of TRPV1, or act in a dominant negative manner when co‐expressed with TRPV1 [322]. The pharmacology of TRPV1 channels is discussed in detail in [117] and [375]. TRPV2 is probably not a thermosensor in man [275], but has recently been implicated in innate immunity [214]. TRPV3 and TRPV4 are both thermosensitive. There are claims that TRPV4 is also mechanosensitive, but this has not been established to be within a physiological range in a native environment [43, 209].

101Under 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 [397, 428]).

102Agents activating TRPA1 in a covalent manner are thiol reactive electrophiles that bind to cysteine and lysine residues within the cytoplasmic domain of the channel [133, 225]. TRPA1 is activated by a wide range of endogenous and exogenous compounds and only a few representative examples are mentioned in the table: an exhaustive listing can be found in [17]. In addition, TRPA1 is potently activated by intracellular zinc (EC50= 8 nM) [11, 140].

103Ca2+ activates all splice variants of TRPM2, but other activators listed are effective only at the full length isoform [87]. Inhibition of TRPM2 by clotrimazole, miconazole, econazole, flufenamic acid is largely irreversible. TRPM4 exists as multiple spice 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 [366]. The V1/2 for activation of TRPM4 and TRPM5 demonstrates a pronounced negative shift with increasing temperature. Activation of TRPM8 by depolarization is strongly temperature‐dependent via a channel‐closing rate that decreases with decreasing temperature. The V1/2 is shifted in the hyperpolarizing direction both by decreasing temperature and by exogenous agonists, such as (‐)‐menthol[371] whereas antagonists produce depolarizing shifts in V1/2[247]. The V1/2 for the native channel is far more positive than that of heterologously expressed TRPM8 [247]. It should be noted that (‐)‐menthol and structurally related compounds can elicit release of Ca2+ from the endoplasmic reticulum independent of activation of TRPM8 [229]. Intracellular pH modulates activation of TRPM8 by cold and icilin, but not (‐)‐menthol[10].

104Data in the table are for TRPML proteins mutated (i.e TRPML1Va, TRPML2Va and TRPML3Va) at loci equivalent to TRPML3 A419P to allow plasma membrane expression when expressed in HEK‐293 cells and subsequent characterisation by patch‐clamp recording [85, 109, 169, 251, 409]. Data for wild type TRPML3 are also tabulated [169, 170, 251, 409]. It should be noted that alternative methodologies, particularly in the case of TRPML1, have resulted in channels with differing biophysical characteristics (reviewed by [297]).

105Data in the table are extracted from [72, 80] and [326]. Broadly similar single channel conductance, mono‐ and di‐valent cation selectivity and sensitivity to blockers are observed for TRPP2 co‐expressed with TRPP1 [79]. 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.

106Activation of TRPV1 by depolarisation is strongly temperature‐dependent via a channel opening rate that increases with increasing temperature. The V1/2 is shifted in the hyperpolarizing direction both by increasing temperature and by exogenous agonists [371]. 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 [266]). 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.

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135Calcium (Ca2+) channels are voltage‐gated ion channels present in the membrane of most excitable cells. The nomenclature for Ca2+channels was proposed by [92] and approved by the NC‐IUPHAR Subcommittee on Ca2+ channels [50]. Ca2+ channels form hetero‐oligomeric complexes. The α1 subunit is pore‐forming and provides the binding site(s) for practically all agonists and antagonists. The 10 cloned α1‐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 the α1s skeletal muscle Cav1.1 channel. The α2‐δ1 and α2‐δ2 subunits bind gabapentin and pregabalin.

136In 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. Both of these physiologically defined current types are conducted by alternative forms of Cav2.1. Ziconotide (a synthetic peptide equivalent to ω‐conotoxin MVIIA) has been approved for the treatment of chronic pain [395].

137The voltage‐gated proton channel (provisionally denoted Hv1) is a putative 4TM proton‐selective channel gated by membrane depolarization and which is sensitive to the transmembrane pH gradient [45, 75, 76, 305, 317]. The structure of Hv1 is homologous to the voltage sensing domain (VSD) of the superfamily of voltage‐gated ion channels (i.e. segments S1 to S4) and contains no discernable pore region [305, 317]. Proton flux through Hv1 is instead most likely mediated by a water wire completed in a crevice of the protein when the voltage‐sensing S4 helix moves in response to a change in transmembrane potential [304, 401]. Hv1 expresses largely as a dimer mediated by intracellular C‐terminal coiled‐coil interactions [208] but individual promoters nonetheless support gated H+ flux via separate conduction pathways [182, 200, 291, 362]. Within dimeric structures, the two protomers do not function independently, but display co‐operative interactions during gating resulting in increased voltage sensitivity, but slower activation, of the dimeric,versus monomeric, complexes [107, 363].

138The voltage threshold (Vthr) for activation of Hv1 is not fixed but is set by the pH gradient across the membrane such that Vthr is positive to the Nernst potential for H+, which ensures that only outwardly directed flux of H+ occurs under physiological conditions [45, 75, 76]. Phosphorylation of Hv1 within the N‐terminal domain by PKC enhances the gating of the channel [245]. Tabulated IC50 values for Zn2+ and Cd2+ are for heterologously expressed human and mouse Hv1 [305, 317]. Zn2+ is not a conventional pore blocker, but is coordinated by two, or more, external protonation sites involving histamine residues [305]. Zn2+ binding may occur at the dimer interface between pairs of histamine residues from both monomers where it may interfere with channel opening [246]. Mouse knockout studies demonstrate that Hv1 participates in charge compensation in granulocytes during the respiratory burst of NADPH oxidase‐dependent reactive oxygen species production that assists in the clearance of bacterial pathogens [306]. Additional physiological functions of Hv1 are reviewed by [45].

139Sodium channels are voltage‐gated sodium‐selective ion channels present in the membrane of most excitable cells. Sodium channels comprise of one pore‐forming α subunit, which may be associated with either one or two β subunits [152]. 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. The crystal structure of the bacterial NavAb channel has revealed a number of novel structural features compared to earlier potassium channel structures including a short selectivity filter with ion selectivity determined by interactions with glutamate side chains [280]. Interestingly, the pore region is penetrated by fatty acyl chains that extend into the central cavity which may allow the entry of small, hydrophobic pore‐blocking drugs [280]. Auxiliary β1, β2, β3 and β4 subunits consist of a large extracellular N‐terminal domain, a single transmembrane segment and a shorter cytoplasmic domain.

140The nomenclature for sodium channels was proposed by Goldin et al., (2000) [105] and approved by the NC‐IUPHAR Subcommittee on sodium channels (Catterall et al., 2005, [48]).

141Sodium channels are also blocked by local anaesthetic agents, antiarrythmic drugs and antiepileptic drugs. In general, these drugs are not highly selective among channel subtypes. 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 fast inactivation (NaV1.8 and particularly NaV1.9 inactivate more slowly). All sodium channels also have a slow inactivation process that is engaged during long depolarizations (>100 msec) or repetitive trains of stimuli. All sodium channel subtypes are blocked by intracellular QX‐314.