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

The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13350/full. Voltage-gated ion channels are one of the eight major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ligand-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates.

Conflict of interest

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

Family structure

5905 CatSper and Two‐Pore channels

5907 Cyclic nucleotide‐regulated channels

5909 Potassium channels

5910 Calcium‐activated potassium channels

5912 Inwardly rectifying potassium channels

5915 Two‐P potassium channels

5917 Voltage‐gated potassium channels

5920 Transient Receptor Potential channels

5934 Voltage‐gated calcium channels

5936 Voltage‐gated proton channel

5937 Voltage‐gated sodium channels

CatSper and Two‐Pore channels

Overview

CatSper channels (CatSper1‐4, nomenclature as agreed by []) are putative 6TM, voltage‐gated, calcium permeant channels that are presumed to assemble as a tetramer of α‐like subunits and mediate the current I[171]. In mammals, CatSper subunits are structurally most closely related to individual domains of voltage‐activated calcium channels (Ca) [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.

Two‐pore channels (TPCs) are structurally related to CatSpers, Cas and Nas. TPCs have a 2x6TM structure with twice the number of TMs of CatSpers and half that of Cas. 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].

Comments

CatSper 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]. I 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 H1, a proton channel [216].

Mutations 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 I and the progesterone response [331]. In addition, certain prostaglandins (e.g. PGF, PGE) also potentiate CatSper mediated currents [215, 343].

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

TPCs 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.

Further Reading

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

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

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

Clapham 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]

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

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

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

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

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

Cyclic nucleotide‐regulated channels

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 [].

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 [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.

CNGA1, CNGA2 and CNGA3 express functional channels as homomers. Three additional subunits (Q8IV77), (Q14028) and (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].

Hyperpolarisation‐activated, cyclic nucleotide‐gated (HCN)

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 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 , I andI . 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 [].

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 [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.

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

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

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

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

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

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

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

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

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

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

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

Hofmann 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]

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

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

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

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

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

Potassium channels

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 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 [, , , ].

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

Bayliss 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]

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

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

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

Goldstein 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]

Gutman 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]

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

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

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

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

Judge 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]

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

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

Kubo 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]

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

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

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

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

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

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

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

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

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

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

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

Wei 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]

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

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

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

Calcium‐activated potassium channels

The 6TM family of K channels comprises the voltage‐gated Ksubfamilies, 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. K1.1 with K1.2; KCNQ2 with KCNQ3).

Inwardly rectifying potassium 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 (K2.x), the G‐protein‐activated inward‐rectifier K channels (K3.x) and the ATP‐sensitive K channels (K6.x, which combine with sulphonylurea receptors (SUR)). The pore‐forming a subunits form tetramers, and heteromeric channels may be formed within subfamilies (e.g. K3.2 with K3.3).

Two‐P potassium channels

The 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. K23.1 with K29.1). 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.

The K27.1, K215.1 and K212.1 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.

Voltage‐gated potassium channels

The 6TM family of K channels comprises the voltage‐gated Ksubfamilies, 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. K1.1 with K1.2; KCNQ2 with KCNQ3).

Transient Receptor Potential channels

The TRP superfamily of channels (nomenclature as agreed by [, ]), 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 IP 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.

TRPA (ankyrin) family

TRPA1 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.

TRPC (canonical) family

Members 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 G‐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].

TRPC1/C4/C5 subgroup

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

TRPC3/C6/C7 subgroup

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

TRPM (melastatin) family

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

TRPM1/M3 subgroup

TRPM1 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].

TRPM2

TRPM2 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].

TRPM4/5 subgroup

TRPM4 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].

TRPM6/7 subgroup

TRPM6 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.

TRPM8

Is 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].

TRPML (mucolipin) family

The 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]).

TRPP (polycystin) family

The 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.

TRPV (vanilloid) family

Members 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.

TRPV1‐V4 subfamily

TRPV1 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].

TRPV5/V6 subfamily

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 [397, 428]).

Agents 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].

Ca2+ 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+] 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].

Data in the table are for TRPML proteins mutated (i.e TRPML1, TRPML2 and TRPML3) 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]).

Data 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.

Activation 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 4 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 P/P 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.

Baraldi PG et al. (2010) Transient receptor potential ankyrin 1 (TRPA1) channel as emerging target for novel analgesics and anti‐inflammatory agents. J. Med. Chem. 53: 5085‐107 [PMID:20356305]

Cheng KT et al. (2011) Contribution of TRPC1 and Orai1 to Ca(2+) entry activated by store depletion. Adv. Exp. Med. Biol. 704: 435‐49 [PMID:21290310]

Clapham DE et al. (2003) International Union of Pharmacology. XLIII. Compendium of voltage‐gated ion channels: transient receptor potential channels. Pharmacol. Rev. 55: 591‐6 [PMID:14657417]

Everaerts W et al. (2010) The vanilloid transient receptor potential channel TRPV4: from structure to disease. Prog. Biophys. Mol. Biol. 103: 2‐17 [PMID:19835908]

Guinamard R et al. (2011) The non‐selective monovalent cationic channels TRPM4 and TRPM5. Adv. Exp. Med. Biol. 704: 147‐71 [PMID:21290294]

Gunthorpe MJ et al. (2009) Clinical development of TRPV1 antagonists: targeting a pivotal point in the pain pathway. Drug Discov. Today 14: 56‐67 [PMID:19063991]

Harteneck C et al. (2011) Pharmacological modulation of diacylglycerol‐sensitive TRPC3/6/7 channels. Curr Pharm Biotechnol 12: 35‐41 [PMID:20932261]

Harteneck C et al. (2011) Synthetic modulators of TRP channel activity. Adv. Exp. Med. Biol. 704: 87‐106 [PMID:21290290]

Islam MS. (2011) TRP channels of islets. Adv. Exp. Med. Biol. 704: 811‐30 [PMID:21290328]

Knowlton WM et al. (2011) TRPM8: from cold to cancer, peppermint to pain. Curr Pharm Biotechnol 12: 68‐77 [PMID:20932257]

Koike C et al. (2010) TRPM1: a vertebrate TRP channel responsible for retinal ON bipolar function. Cell Calcium 48: 95‐101 [PMID:20846719]

Liu Y et al. (2011) TRPM8 in health and disease: cold sensing and beyond. Adv. Exp. Med. Biol. 704: 185‐208 [PMID:21290296]

Mälkiä A et al. (2011) The emerging pharmacology of TRPM8 channels: hidden therapeutic potential underneath a cold surface. Curr Pharm Biotechnol 12: 54‐67 [PMID:20932258]

Nilius B et al. (2010) Transient receptor potential channelopathies. Pflugers Arch. 460: 437‐50 [PMID:20127491]

Nilius B et al. (2007) Transient receptor potential cation channels in disease. Physiol. Rev. 87: 165‐217 [PMID:17237345]

Owsianik G et al. (2006) Permeation and selectivity of TRP channels. Annu. Rev. Physiol. 68: 685‐717 [PMID:16460288]

Ramsey IS et al. (2006) An introduction to TRP channels. Annu. Rev. Physiol. 68: 619‐47 [PMID:16460286]

Rohacs T. (2009) Phosphoinositide regulation of non‐canonical transient receptor potential channels. Cell Calcium 45: 554‐65 [PMID:19376575]

Runnels LW. (2011) TRPM6 and TRPM7: A Mul‐TRP‐PLIK‐cation of channel functions. Curr Pharm Biotechnol 12: 42‐53 [PMID:20932259]

Vay L et al. (2011) The thermo‐TRP ion channel family: properties and therapeutic implications. Br J Pharmacol [PMID:21797839]

Vennekens R et al. (2008) Vanilloid transient receptor potential cation channels: an overview. Curr. Pharm. Des. 14: 18‐31 [PMID:18220815]

Vincent F et al. (2011) TRPV4 agonists and antagonists. Curr Top Med Chem 11: 2216‐26 [PMID:21671873]

Vriens J et al. (2009) Pharmacology of vanilloid transient receptor potential cation channels. Mol. Pharmacol. 75: 1262‐79 [PMID:19297520]

Wu LJ et al. (2010) International Union of Basic and Clinical Pharmacology. LXXVI. Current progress in the mammalian TRP ion channel family. Pharmacol. Rev. 62: 381‐404 [PMID:20716668]

Yamamoto S et al. (2010) Chemical physiology of oxidative stress‐activated TRPM2 and TRPC5 channels. Prog. Biophys. Mol. Biol. 103: 18‐27 [PMID:20553742]

Yuan JP et al. (2009) TRPC channels as STIM1‐regulated SOCs. Channels (Austin) 3: 221‐5 [PMID:19574740]

Zeevi DA et al. (2007) TRPML and lysosomal function. Biochim. Biophys. Acta 1772: 851‐8 [PMID:17306511]

Zholos A. (2010) Pharmacology of transient receptor potential melastatin channels in the vasculature. Br. J. Pharmacol. 159: 1559‐71 [PMID:20233227]

Voltage‐gated calcium channels

Calcium (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 []. 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, Ca1.x) channels; (2) the high‐voltage activated dihydropyridine‐insensitive (Ca2.x) channels and (3) the low‐voltage‐activated (T‐type, Ca3.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.

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

Voltage‐gated proton channel

The voltage‐gated proton channel (provisionally denoted H1) 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 H1 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 H1 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]. H1 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] .

The voltage threshold (V) for activation of Hv1 is not fixed but is set by the pH gradient across the membrane such that V 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 H1 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 H1 [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 H1 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 H1 are reviewed by [45].

Voltage‐gated sodium channels

Sodium 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.

The nomenclature for sodium channels was proposed by Goldin [] and approved by the []).

Sodium 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(Na1.5, Na1.8 and Na1.9 are much less sensitive to block) and rate of fast inactivation (Na1.8 and particularly Na1.9 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.

Nomenclature	CatSper1
HGNC, UniProt	CATSPER1, Q8NEC5
Activators	CatSper1 is constitutively active, weakly facilitated by membrane depolarisation, strongly augmented by intracellular alkalinisation. In human, but not mouse, spermatozoa progesterone (EC50   8 nM) also potentiates the CatSper current (ICatSper). [215, 343]
Functional Characteristics	Calcium selective ion channel (Ba2+>Ca2+≫Mg2+≫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 (mouse); V1/2 @ pH 7.5 = +11mV (mouse) or pH 7.4 = +85 mV (human)]; required for ICatSper and male fertility (mouse and human)
Channel blockers	ruthenium red (Inhibition) (pIC50 5) [171] – Mouse, HC‐056456 (pIC50 4.7) [46], Cd2+ (Inhibition) (pIC50 3.7) [171] – Mouse, Ni2+ (Inhibition) (pIC50 3.5) [171] – Mouse
Selective channel blockers	NNC55‐0396 (Inhibition) (pIC50 5.7) [‐80mV – 80mV] [215, 343], mibefradil (Inhibition) (pIC50 4.4–4.5) [343]

Nomenclature	CatSper2	CatSper3	CatSper4
HGNC, UniProt	CATSPER2, Q96P56	CATSPER3, Q86XQ3	CATSPER4, Q7RTX7
Functional Characteristics	Required for ICatSper and male fertility(mouse and human)	Required for ICatSper and male fertility (mouse)	Required for ICatSper and male fertility (mouse)

Nomenclature	TPC1	TPC2
HGNC, UniProt	TPCN1, Q9ULQ1	TPCN2, Q8NHX9
Functional Characteristics	Organelle voltage‐gated Na+‐selective channel (Na+≫K+≫Ca2+); Required for the generation of action potential‐like long depolarization in lysosomes. Voltage‐dependence of activation is sensitive to luminal pH (determined from lysosomal recordings). ψ 1/2 @ pH4.6 = +91 mV; ψ 1/2 @ pH6.5 = +2.6 mV. Maximum activity requires PI(3,5)P2 and reduced [ATP]	Organelle voltage‐independent Na+‐selective channel (Na+≫K+≫Ca2+). Sensitive to the levels of PI(3,5)P2. Activated by decreases in [ATP] or depletion of extracellular amino acids
Activators	phosphatidyl (3,5) inositol bisphosphate (pEC50 6.5) [41]	phosphatidyl (3,5) inositol bisphosphate (pEC50 6.4) [387]
Channel blockers	verapamil (Inhibition) (pIC50 4.6) [41], Cd2+ (Inhibition) (pIC50 3.7) [41]	verapamil (Inhibition) (pIC50 5) [387]

Nomenclature	CNGA1	CNGA2	CNGA3	CNGB3
HGNC, UniProt	CNGA1, P29973	CNGA2, Q16280	CNGA3, Q16281	CNGB3, Q9NQW8
Activators	cyclic GMP (EC50   30 μM) ≫cyclic AMP	cyclic GMP   cyclic AMP (EC50   1 μM)	cyclic GMP (EC50   30 μM) ≫cyclic AMP	–
Functional Characteristics	γ = 25‐30 pS P Ca/P Na = 3.1	γ = 35 pS P Ca/P Na = 6.8	γ = 40 pS P Ca/P Na = 10.9	–
Inhibitors	–	–	L‐(cis)‐diltiazem	–
Channel blockers	dequalinium (Antagonist) (pIC50 6.7) [0mV] [312], L‐(cis)‐diltiazem (Antagonist) (pK i 4) [‐80mV – 80mV] [53]	dequalinium (Antagonist) (pIC50 5.6) [0mV] [311]	–	L‐(cis)‐diltiazem (Antagonist) (pIC50 5.5) [0mV] [102] – Mouse

Nomenclature	HCN1	HCN2	HCN3	HCN4
HGNC, UniProt	HCN1, O60741	HCN2, Q9UL51	HCN3, Q9P1Z3	HCN4, Q9Y3Q4
Activators	cyclic AMP>cyclic GMP (both weak)	cyclic AMP>cyclic GMP	–	cyclic AMP>cyclic GMP
Channel blockers	ivabradine (Antagonist) (pIC50 5.7) [‐40mV] [337], ZD7288 (Antagonist) (pIC50 4.7) [‐40mV] [336], Cs+ (Antagonist) (pIC50 3.7) [‐40mV] [336]	ivabradine (Antagonist) (pIC50 5.6) [‐40mV] [337] – Mouse, ZD7288 (Antagonist) (pIC50 4.4) [‐40mV] [336], Cs+ (Antagonist) (pIC50 3.7) [‐40mV] [336]	ivabradine (Antagonist) (pIC50 5.7) [‐40mV] [337], ZD7288 (Antagonist) (pIC50 4.5) [‐40mV] [336], Cs+ (Antagonist) (pIC50 3.8) [‐40mV] [336]	ivabradine (Antagonist) (pIC50 5.7) [‐40mV] [337], ZD7288 (Antagonist) (pIC50 4.7) [‐40mV] [336], Cs+ (Antagonist) (pIC50 3.8) [‐40mV] [336]

Nomenclature	KCa1.1	KCa2.1	KCa2.2	KCa2.3
HGNC, UniProt	KCNMA1, Q12791	KCNN1, Q92952	KCNN2, Q9H2S1	KCNN3, Q9UGI6
Functional Characteristics	Maxi KCa	SKCa	SKCa	SKCa
Activators	NS004, NS1619	EBIO (Agonist) Concentration range: 2 × 10−3M [‐80mV] [284, 390], NS309 (Agonist) Concentration range: 3 × 10−8M‐1 × 10−7M [‐90mV] [341, 390]	NS309 (Agonist) (pEC50 6.2) Concentration range: 3 × 10−8M‐1 × 10−7M [‐90mV – ‐50mV] [283, 341, 390], EBIO (Agonist) (pEC50 3.3) [‐50mV] [283, 390], EBIO (Agonist) (pEC50 3) Concentration range: 2 × 10−3M [‐100mV] [44, 284] – Rat	EBIO (Agonist) (pEC50 3.8) [‐160mV – ‐120mV] [390, 398], NS309 (Agonist) Concentration range: 3 × 10−8M [‐90mV] [341, 390]
Inhibitors	charybdotoxin, iberiotoxin, tetraethylammonium	–	–	–
Channel blockers	paxilline (Antagonist) (pK i 8.7) [0mV] [316] – Mouse	UCL1684 (Antagonist) (pIC50 9.1) [‐80mV] [340, 390], apamin (Antagonist) (pIC50 7.9–8.5, median 8.1) [‐80mV] [323, 338, 340], tetraethylammonium (Antagonist) (pIC50 2.7) [390]	UCL1684 (Antagonist) (pIC50 9.6) [‐40mV] [94, 390], apamin (Antagonist) (pK d 9.4) [‐80mV] [161], tetraethylammonium (Antagonist) (pIC50 2.7) [390]	apamin (Antagonist) (pIC50 7.9–9.1) [‐160mV – ‐100mV] [358, 398], UCL1684 (Antagonist) (pIC50 8–9) [‐80mV] [94, 390], tetraethylammonium (Antagonist) (pIC50 2.7) [390]
Comments	–	The rat isoform does not form functional channels when expressed alone in cell lines. N‐ or C‐terminal chimeric constructs permit functional channels that are insensitive to apamin [390]. Heteromeric channels are formed between KCa2.1 and 2.2 subunits that show intermediate sensitivity to apamin [63].	–	–

Nomenclature	KCa3.1	KNa1.1	KNa1.2	KCa5.1
HGNC, UniProt	KCNN4, O15554	KCNT1, Q5JUK3	KCNT2, Q6UVM3	KCNU1, A8MYU2
Functional Characteristics	IKCa	KNa	KNa	Sperm pH‐regulated K+ current, KSPER
Activators	NS309 (Agonist) (pEC50 8) [‐90mV] [341, 390], SKA‐121 (Agonist) (pEC50 7) [67], EBIO (Agonist) (pEC50 4.1–4.5) [‐100mV – ‐50mV] [284, 346, 390]	bithionol (Agonist) (pEC50 5–6) [414] – Rat, niclosamide (Agonist) (pEC50 5.5) [30], loxapine (Agonist) (pEC50 5.4) [30]	niflumic acid (Agonist) [71]	–
Gating inhibitors	–	bepridil (Antagonist) (pIC50 5–6) [9, 27, 414] – Rat	–	–
Channel blockers	charybdotoxin (Inhibition) (pIC50 7.6–8.7) [153, 157], TRAM‐34 (Inhibition) (pK d 7.6–8) [193, 403]	quinidine (Antagonist) (pIC50 4) [414] – Rat	Ba2+ (Inhibition) (pIC50 3) [27], quinidine (Inhibition) Concentration range: 1 × 10−3M [27] – Rat	tetraethylammonium (pEC50 2.3) [319, 355] – Mouse, quinidine [355] – Mouse

Nomenclature	Kir1.1	Kir2.1	Kir2.2
HGNC, UniProt	KCNJ1, P48048	KCNJ2, P63252	KCNJ12, Q14500
Ion Selectivity and Conductance	NH4 + [62pS] > K+ [38. pS] > Tl+ [21pS] > Rb+ [15pS] (Rat) [57, 134]	–	–
Functional Characteristics	Kir1.1 is weakly inwardly rectifying, as compared to classical (strong) inward rectifiers.	IK1 in heart, ‘strong’ inward‐rectifier current	IK1in heart, ‘strong’ inward‐rectifier current
Endogenous activators	–	PIP2 (Agonist) Concentration range: 1 × 10−5M‐5 × 10−5M [‐30mV] [142, 307, 334] – Mouse	–
Endogenous inhibitors	–	–	Intracellular Mg2+ (pIC50 5) [40mV] [413]
Gating inhibitors	–	–	Ba2+ (Antagonist) Concentration range: 5 × 10−5M [‐150mV – ‐50mV] [349] – Mouse, Cs+ (Antagonist) Concentration range: 5 × 10−6M‐5 × 10−5M [‐150mV – ‐50mV] [349] – Mouse
Endogenous channel blockers	–	spermine (Antagonist) (pK d 9.1) [voltage dependent 40mV] [150, 415] – Mouse, spermidine (Antagonist) (pK d 8.1) [voltage dependent 40mV] [415] – Mouse, putrescine (Antagonist) (pK d 5.1) [voltage dependent 40mV] [150, 415] – Mouse, Intracellular Mg2+ (Antagonist) (pK d 4.8) [voltage dependent 40mV] [415] – Mouse	–
Channel blockers	tertiapin‐Q (Inhibition) (pIC50 8.9) [156], Ba2+ (Antagonist) (pIC50 2.3–4.2) Concentration range: 1 × 10−4M [voltage dependent 0mV – ‐100mV] [134, 424] – Rat, Cs+ (Antagonist) (pIC50 2.9) [voltage dependent ‐120mV] [424] – Rat	Ba2+ (Antagonist) (pK d 3.9–5.6) Concentration range: 1 × 10−6M‐1 × 10−4M [voltage dependent 0mV – ‐80mV] [6] – Mouse, Cs+ (Antagonist) (pK d 1.3–4) Concentration range: 3 × 10−5M‐3 × 10−4M [voltage dependent 0mV – ‐102mV] [3] – Mouse	–
Comments	–	Kir2.1 is also inhibited by intracellular polyamines	Kir2.2 is also inhibited by intracellular polyamines

Nomenclature	Kir2.3	Kir2.4	Kir3.1	Kir3.2
HGNC, UniProt	KCNJ4, P48050	KCNJ14, Q9UNX9	KCNJ3, P48549	KCNJ6, P48051
Functional Characteristics	IK1 in heart, ‘strong’ inward‐rectifier current	IK1 in heart, ‘strong’ inward‐rectifier current	G‐protein‐activated inward‐rectifier current	G‐protein‐activated inward‐rectifier current
Endogenous activators	–	–	PIP2 (Agonist) (pK d 6.3) Concentration range: 5 × 10−5M [physiological voltage] [142] – Unknown	PIP2 (Agonist) (pK d 6.3) Concentration range: 5 × 10−5M [physiological voltage] [142] – Unknown
Endogenous inhibitors	–	Intracellular Mg2+	–	–
Gating inhibitors	–	–	–	pimozide (Antagonist) (pEC50 5.5) [‐70mV] [180] – Mouse
Endogenous channel blockers	Intracellular Mg2+ (Antagonist) (pK d 5) [voltage dependent 50mV] [222], putrescine (Antagonist) Concentration range: 5 × 10−5M‐1 × 10−3M [‐80mV – 80mV] [222], spermidine (Antagonist) Concentration range: 2.5 × 10−5M‐1 × 10−3M [‐80mV – 80mV] [222], spermine (Antagonist) Concentration range: 5 × 10−5M‐1 × 10−3M [‐80mV – 80mV] [222]	–	–	–
Channel blockers	Ba2+ (Antagonist) (pIC50 5) Concentration range: 3 × 10−6M‐5 × 10−4M [‐60mV] [233, 296, 356], Cs+ (Antagonist) (pK i 1.3–4.5) Concentration range: 3 × 10−6M‐3 × 10−4M [0mV – ‐130mV] [233]	Cs+ (Antagonist) (pK d 3–4.1) [voltage dependent ‐60mV – ‐100mV] [143], Ba2+ (Antagonist) (pK d 3.3) [voltage dependent 0mV] [143]	tertiapin‐Q (Antagonist) (pIC50 7.9) [156], Ba2+ (Antagonist) (pIC50 4.7) [73] – Rat	desipramine (Antagonist) (pIC50 4.4) [‐70mV] [181] – Mouse
Comments	Kir2.3 is also inhibited by intracellular polyamines	Kir2.4 is also inhibited by intracellular polyamines	Kir3.1 is also activated by Gβγ. Kir3.1 is not functional alone. The functional expression of Kir3.1 in Xenopus oocytes requires coassembly with the endogenous Xenopus Kir3.5 subunit. The major functional assembly in the heart is the Kir3.1/3.4 heteromultimer, while in the brain it is Kir3.1/3.2, Kir3.1/3.3 and Kir3.2/3.3.	Kir3.2 is also activated by Gβγ. Kir3.2 forms functional heteromers with Kir3.1/3.3.

Nomenclature	Kir3.3	Kir3.4	Kir4.1	Kir4.2
HGNC, UniProt	KCNJ9, Q92806	KCNJ5, P48544	KCNJ10, P78508	KCNJ15, Q99712
Functional Characteristics	G‐protein‐activated inward‐rectifier current	G‐protein‐activated inward‐rectifier current	Inward‐rectifier current	Inward‐rectifier current
Endogenous activators	PIP2 [129]	PIP2 [20, 129]	–	–
Channel blockers	–	tertiapin‐Q (Antagonist) (pIC50 7.9) [156]	Ba2+ (Antagonist) Concentration range: 3 × 10−6M‐1 × 10−3M [‐160mV – 60mV] [185, 351, 354] – Rat, Cs+ (Antagonist) Concentration range: 3 × 10−5M‐3 × 10−4M [‐160mV – 50mV] [351] – Rat	Ba2+ (Antagonist) Concentration range: 1 × 10−5M‐1 × 10−4M [‐120mV – 100mV] [282] – Mouse, Cs+ (Antagonist) Concentration range: 1 × 10−5M‐1 × 10−4M [‐120mV – 100mV] [282] – Mouse
Comments	Kir3.3 is also activated by Gβγ	Kir3.4 is also activated by Gβγ	–	–

Nomenclature	Kir5.1	Kir6.1	Kir6.2	Kir7.1
HGNC, UniProt	KCNJ16, Q9NPI9	KCNJ8, Q15842	KCNJ11, Q14654	KCNJ13, O60928
Associated subunits	–	SUR1, SUR2A, SUR2B	SUR1, SUR2A, SUR2B	–
Functional Characteristics	Weakly inwardly rectifying	ATP‐sensitive, inward‐rectifier current	ATP‐sensitive, inward‐rectifier current	Inward‐rectifier current
Activators	–	cromakalim, diazoxide (Agonist) Concentration range: 2 × 10−4M [‐60mV] [411] – Mouse, minoxidil, nicorandil (Agonist) Concentration range: 3 × 10−4M [‐60mV – 60mV] [411] – Mouse	diazoxide (Agonist) (pEC50 4.2) [physiological voltage] [146] – Mouse, cromakalim (Agonist) Concentration range: 3 × 10−5M [‐60mV] [147] – Mouse, minoxidil, nicorandil	–
Inhibitors	–	glibenclamide, tolbutamide	glibenclamide, tolbutamide	–
Channel blockers	Ba2+ (Antagonist) Concentration range: 3 × 10−3M [‐120mV – 20mV] [353] – Rat	–	–	Ba2+ (Antagonist) (pK i 3.2) [voltage dependent ‐100mV] [90, 190, 192, 277], Cs+ (Antagonist) (pK i 1.6) [voltage dependent ‐100mV] [90, 190, 277]

Nomenclature	K2P1.1	K2P2.1	K2P3.1	K2P4.1	K2P5.1
HGNC, UniProt	KCNK1, O00180	KCNK2, O95069	KCNK3, O14649	KCNK4, Q9NYG8	KCNK5, O95279
Functional Characteristics	Background current	Background current	Background current. Knock‐out of the kcnk3 gene leads to a prolonged QT interval in mice [77].	Background current	Background current
Endogenous activators	–	arachidonic acid (pEC50 5)	–	arachidonic acid (Positive) Concentration range: 5 × 10−6M‐5 × 10−5M [168] – Rat	–
Activators	–	halothane, riluzole	halothane (Positive) (pEC50 3) Concentration range: 1 × 10−3M [389] – Rat	riluzole (Positive) Concentration range: 3 × 10−6M‐1 × 10−4M [88]	–
Channel blockers	–	–	anandamide (Inhibition) (pIC50 5.6) [230]	–	–
Comments	K2P1.1 is inhibited by acid pHo	K2P2.1 is also activated by stretch, heat and acid pHi	K2P3.1 is also activated by alkaline pHo and inhibited by acid pHo	K2P4.1 is also activated by heat, acid pHi, and membrane stretch	K2P5.1 is activated by alkaline pHo

Nomenclature	K2P6.1	K2P7.1	K2P9.1	K2P10.1	K2P12.1
HGNC, UniProt	KCNK6, Q9Y257	KCNK7, Q9Y2U2	KCNK9, Q9NPC2	KCNK10, P57789	KCNK12, Q9HB15
Functional Characteristics	Unknown	Unknown	Background current	Background current	Unknown
Endogenous activators	–	–	–	arachidonic acid [203]	–
Activators	–	–	halothane	halothane, riluzole	–
Inhibitors	–	–	anandamide, ruthenium red	–	halothane
Comments	–	–	K2P9.1 is also inhibited by acid pHo	K2P10.1 is also activated by heat, acid pHi, and membrane stretch	–

Nomenclature	K2P13.1	K2P15.1	K2P16.1	K2P17.1	K2P18.1
HGNC, UniProt	KCNK13, Q9HB14	KCNK15, Q9H427	KCNK16, Q96T55	KCNK17, Q96T54	KCNK18, Q7Z418
Functional Characteristics	Background current	Unknown	Background current	Background current	Background current
Endogenous inhibitors	–	–	–	–	arachidonic acid
Inhibitors	halothane	–	–	–	–
Comments	–	–	K2P16.1 is activated by alkaline pHo	K2P17.1 is activated by alkaline pHo	–

Nomenclature	Kv1.1	Kv1.2	Kv1.3	Kv1.4	Kv1.5
HGNC, UniProt	KCNA1, Q09470	KCNA2, P16389	KCNA3, P22001	KCNA4, P22459	KCNA5, P22460
Associated subunits	Kv1.2, Kv1.4, Kv β1 and Kv β2 [68]	Kv1.1, Kv1.4, Kv β1 and Kv β2 [68]	Kv1.1, Kv1.2, Kv1.4, Kv1.6 , Kv β1 and Kv β2 [68]	Kv1.1, Kv1.2, Kv β1 and Kv β2 [68]	Kv β1 and Kv β2
Functional Characteristics	KV	KV	KV	KA	KV
Channel blockers	α‐dendrotoxin (pEC50 7.7–9) [113, 144] – Rat, margatoxin (Inhibition) (pIC50 8.4) [19], tetraethylammonium (Inhibition) (pK d 3.5) [113] – Mouse	margatoxin (Inhibition) (pIC50 11.2) [19], α‐dendrotoxin (pIC50 7.8–9.4) [113, 144] – Rat, noxiustoxin (pK d 8.7) [113] – Rat	margatoxin (pIC50 10–10.3) [100, 103], noxiustoxin (pK d 9) [113] – Mouse, tetraethylammonium (moderate) (pK d 2) [113] – Mouse	fampridine (pIC50 1.9) [344] – Rat	–
Selective channel blockers	–	–	correolide (pIC50 7.1) [95]	–	–

Nomenclature	Kv1.6	Kv1.7	Kv1.8	Kv2.1	Kv2.2
HGNC, UniProt	KCNA6, P17658	KCNA7, Q96RP8	KCNA10, Q16322	KCNB1, Q14721	KCNB2, Q92953
Associated subunits	Kv β1 and Kv β2	Kv β1 and Kv β2	Kv β1 and Kv β2	Kv5.1, Kv6.1‐6.4, Kv8.1‐8.2 and Kv9.1‐9.3	Kv5.1, Kv6.1‐6.4, Kv8.1‐8.2 and Kv9.1‐9.3
Functional Characteristics	KV	KV	KV	KV	–
Channel blockers	α‐dendrotoxin (pIC50 7.7) [114], tetraethylammonium (pIC50 2.2) [114]	fampridine (pIC50 3.6) [162] – Mouse	fampridine (pIC50 2.8) [195]	tetraethylammonium (Pore blocker) (pIC50 2) [127] – Rat	fampridine (pIC50 2.8) [318], tetraethylammonium (pIC50 2.6) [318]

Nomenclature	Kv3.1	Kv3.2	Kv3.3	Kv3.4	Kv4.1
HGNC, UniProt	KCNC1, P48547	KCNC2, Q96PR1	KCNC3, Q14003	KCNC4, Q03721	KCND1, Q9NSA2
Associated subunits	–	–	–	MiRP2 is an associated subunit for Kv3.4	KChIP and KChAP
Functional Characteristics	KV	KV	KA	KA	KA
Channel blockers	fampridine (pIC50 4.5) [113] – Mouse, tetraethylammonium (pIC50 3.7) [113] – Mouse	fampridine (pIC50 4.6) [210] – Rat, tetraethylammonium (pIC50 4.2) [210] – Rat	tetraethylammonium (pIC50 3.9) [367] – Rat	tetraethylammonium (pIC50 3.5) [309, 321] – Rat	fampridine (pIC50 2) [149]
Selective channel blockers	–	–	–	sea anemone toxin BDS‐I (pIC50 7.3) [84] – Rat	–

Nomenclature	Kv4.2	Kv4.3	Kv5.1	Kv6.1	Kv6.2	Kv6.3	Kv6.4
HGNC, UniProt	KCND2, Q9NZV8	KCND3, Q9UK17	KCNF1, Q9H3M0	KCNG1, Q9UIX4	KCNG2, Q9UJ96	KCNG3, Q8TAE7	KCNG4, Q8TDN1
Associated subunits	KChIP and KChAP	KChIP and KChAP	–	–	–	–	–
Functional Characteristics	KA	KA	–	–	–	–	–

Nomenclature	Kv7.1	Kv7.2	Kv7.3	Kv7.4	Kv7.5
HGNC, UniProt	KCNQ1, P51787	KCNQ2, O43526	KCNQ3, O43525	KCNQ4, P56696	KCNQ5, Q9NR82
Functional Characteristics	cardiac IK5	M current	M current	–	–
Activators	–	retigabine (pEC50 5.6) [357]	retigabine (pEC50 6.2) [357]	retigabine (pEC50 5.2) [357]	retigabine (pEC50 5) [89]
Inhibitors	linopirdine (pIC50 4.4) [271] – Mouse	–	linopirdine (pIC50 5.4) [385] – Rat	–	–
Channel blockers	XE991 (Antagonist) (pK d 6.1) [384]	XE991 (pIC50 6.2) [385], linopirdine (pIC50 5.3) [385], tetraethylammonium (pIC50 3.5–3.9) [121, 394]	–	XE991 (pIC50 5.3) [348], linopirdine (pIC50 4.9) [348], tetraethylammonium (pIC50 1.3) [14]	linopirdine (pK d 4.8) [202]
(Sub)family‐selective channel blockers	–	–	–	–	XE991 (pIC50 4.2) [320]

Nomenclature	Kv8.1	Kv8.2	Kv9.1	Kv9.2	Kv9.3	Kv10.1	Kv10.2
HGNC, UniProt	KCNV1, Q6PIU1	KCNV2, Q8TDN2	KCNS1, Q96KK3	KCNS2, Q9ULS6	KCNS3, Q9BQ31	KCNH1, O95259	KCNH5, Q8NCM2

Nomenclature	Kv11.1	Kv11.2	Kv11.3	Kv12.1	Kv12.2	Kv12.3
HGNC, UniProt	KCNH2, Q12809	KCNH6, Q9H252	KCNH7, Q9NS40	KCNH8, Q96L42	KCNH3, Q9ULD8	KCNH4, Q9UQ05
Associated subunits	minK (KCNE1) and MiRP1 (KCNE2)	minK (KCNE1)	minK (KCNE1)	minK (KCNE1)	minK (KCNE1) and MiRP2 (KCNE3)	–
Functional Characteristics	cardiac IKR	–	–	–	–	–
Channel blockers	astemizole (pIC50 9) [426], terfenadine (pIC50 7.3) [303], disopyramide (Inhibition) (pIC50 4) [167]	–	–	–	–	–
(Sub)family‐selective channel blockers	E4031 (pIC50 8.1) [425]	–	–	–	–	–
Selective channel blockers	dofetilide (Inhibition) (pK i 8.2) [328], ibutilide (pIC50 7.6–8) [167, 290]	–	–	–	–	–
Comments	RPR260243 is an activator of Kv11.1 [163].	–	–	–	–	–

Nomenclature	TRPA1
HGNC, UniProt	TRPA1, O75762
Chemical activators	–
Other chemical activators	Isothiocyanates (covalent) and 1,4‐dihydropyridines (non‐covalent)
Physical activators	Cooling (<17∘C) (disputed)
Functional Characteristics	γ = 87‐100 pS; conducts mono‐ and di‐valent cations non‐selectively (PCa/PNa = 0.84); outward rectification; activated by elevated intracellular Ca2+
Activators	acrolein (Agonist) (pEC50 5.3) [physiological voltage] [21], allicin (Agonist) (pEC50 5.1) [physiological voltage] [22], Δ9‐tetrahydrocannabinol (Agonist) (pEC50 4.9) [‐60mV] [158], nicotine (non‐covalent) (pEC50 4.8) [‐75mV] [352], thymol (non‐covalent) (pEC50 4.7) Concentration range: 6.2 × 10−6M‐2.5 × 10−5M [199], URB597 (Agonist) (pEC50 4.6) [257], (‐)‐menthol (Partial agonist) (pEC50 4–4.5) [164, 405], cinnamaldehyde (Agonist) (pEC50 4.2) [physiological voltage] [15] – Mouse, icilin (Agonist) Concentration range: 1 × 10−4M [physiological voltage] [339] – Mouse
Selective activators	chlorobenzylidene malononitrile (covalent) (pEC50 6.7) [37], formalin (covalent. This level of activity is also observed for rat TRPA1) (pEC50 3.4) [228, 238] – Mouse
Channel blockers	AP18 (Inhibition) (pIC50 5.5) [292], ruthenium red (Inhibition) (pIC50 5.5) [‐80mV] [250] – Mouse, HC030031 (Inhibition) (pIC50 5.2) [238]

Nomenclature	TRPC1	TRPC2	TRPC3
HGNC, UniProt	TRPC1, P48995	TRPC2, –	TRPC3, Q13507
Chemical activators	NO‐mediated cysteine S‐nitrosation	–	diacylglycerols
Physical activators	membrane stretch (likely direct)	–
Functional Characteristics	It is not yet clear that TRPC1 forms a homomer. It does form heteromers with TRPC4 and TRPC5	–	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
Activators	–	DOG (Agonist) Concentration range: 1 × 10−4M [‐80mV] [223] – Mouse, SAG (Agonist) Concentration range: 1 × 10−4M [‐80mV] [223] – Mouse	–
Channel blockers	2‐APB (Antagonist) [‐70mV] [342], Gd3+ (Antagonist) Concentration range: 2 × 10−5M [‐70mV] [427], GsMTx‐4, La3+ (Antagonist) Concentration range: 1 × 10−4M [‐70mV] [342], SKF96365	2‐APB (Antagonist) Concentration range: 5 × 10−5M [‐70mV – 80mV] [223] – Mouse	Gd3+ (Antagonist) (pEC50 7) [‐60mV] [122], BTP2 (Antagonist) (pIC50 6.5) [‐80mV] [126], La3+ (Antagonist) (pIC50 5.4) [‐60mV] [122], 2‐APB (Antagonist) (pIC50 5) [physiological voltage] [211], ACAA, KB‐R7943, Ni2+, Pyr3 [175], SKF96365

Nomenclature	TRPC4	TRPC5	TRPC6	TRPC7
HGNC, UniProt	TRPC4, Q9UBN4	TRPC5, Q9UL62	TRPC6, Q9Y210	TRPC7, Q9HCX4
Chemical activators	–	–	–	diacylglycerols
Other chemical activators	NO‐mediated cysteine S‐nitrosation, potentiation by extracellular protons	NO‐mediated cysteine S‐nitrosation (disputed), potentiation by extracellular protons	Diacylglycerols	–
Physical activators	–	Membrane stretch (likely indirect)	Membrane stretch (likely indirect)	–
Functional Characteristics	γ = 30 ‐41 pS, conducts mono and di‐valent cations non‐selectively (PCa/PNa = 1.1 ‐ 7.7); dual (inward and outward) rectification	γ = 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	γ = 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	γ = 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+
Endogenous activators	–	intracellular Ca2+ (at negative potentials) (pEC50 6.2), lysophosphatidylcholine	20‐HETE, arachidonic acid, lysophosphatidylcholine	–
Activators	La3+ (μM range)	Gd3+ Concentration range: 1 × 10−4M, La3+ (μM range), Pb2+ Concentration range: 5 × 10−6M, daidzein, genistein (independent of tyrosine kinase inhibition) [400]	flufenamate, hyp 9 [204], hyperforin [205]	–
Endogenous channel blockers	–	–	–	–
Channel blockers	ML204 (pIC50 5.5) [240], 2‐APB, La3+ (mM range), SKF96365, niflumic acid (Antagonist) Concentration range: 3 × 10−5M [‐60mV] [380] – Mouse	KB‐R7943 (Inhibition) (pIC50 5.9) [187], ML204 (pIC50∼5) [240], 2‐APB (Antagonist) (pIC50 4.7) [‐80mV] [410], BTP2, GsMTx‐4, La3+ (Antagonist) Concentration range: 5 × 10−3M [‐60mV] [159] – Mouse, SKF96365, chlorpromazine, flufenamic acid	Gd3+ (Antagonist) (pIC50 5.7) [‐60mV] [148] – Mouse, SKF96365 (Antagonist) (pIC50 5.4) [‐60mV] [148] – Mouse, La3+ (pIC50∼5.2), amiloride (Antagonist) (pIC50 3.9) [‐60mV] [148] – Mouse, Cd2+ (Antagonist) (pIC50 3.6) [‐60mV] [148] – Mouse, 2‐APB, ACAA, GsMTx‐4, Extracellular H+, KB‐R7943, ML9	2‐APB, La3+ (Antagonist) Concentration range: 1 × 10−4M [‐60mV] [272] – Mouse, SKF96365 (Antagonist) Concentration range: 2.5 × 10−5M [‐60mV] [272] – Mouse, amiloride

Nomenclature	TRPM1	TRPM2	TRPM3	TRPM4
HGNC, UniProt	TRPM1, Q7Z4N2	TRPM2, O94759	TRPM3, Q9HCF6	TRPM4, Q8TD43
Other channel blockers	–	–	–	Intracellular nucleotides including ATP, adenosine diphosphate, adenosine 5'‐monophosphate and AMP‐PNP with an IC50 range of 1.3‐1.9 μM
Other chemical activators	–	Agents producing reactive oxygen (e.g. H2O2) and nitrogen (e.g. GEA 3162) species	–	–
Physical activators	–	Heat   35∘C	heat (Q10 = 7.2 between 15 ‐ 25∘C; Vriens et al., 2011), hypotonic cell swelling [376]	Membrane depolarization (V1/2 = ‐20 mV to + 60 mV dependent upon conditions) in the presence of elevated [Ca2+]i, heat (Q10 = 8.5 @ +25 mV between 15 and 25∘C)
Functional Characteristics	Conducts mono‐ and di‐valent cations non‐selectively, dual rectification (inward and outward)	γ = 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 inhibitors	TRPM31235: 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)	γ = 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
Endogenous activators	pregnenolone sulphate [194]	intracellular cADPR (Agonist) (pEC50 5) [‐80mV – ‐60mV] [24, 184, 360], intracellular ADP ribose (Agonist) (pEC50 3.9–4.4) [‐80mV] [289], intracellular Ca2+ (via calmodulin), H2O2 (Agonist) Concentration range: 5 × 10−7M‐5 × 10−5M [physiological voltage] [98, 123, 189, 332, 391], arachidonic acid (Potentiation) Concentration range: 1 × 10−5M‐3 × 10−5M [physiological voltage] [123]	sphingosine (Agonist) (pEC50 4.9) [physiological voltage] [112], epipregnanolone sulphate [231], pregnenolone sulphate [377], sphinganine (Agonist) Concentration range: 2 × 10−5M [physiological voltage] [112]	intracellular Ca2+ (Agonist) (pEC50 3.9–6.3) [‐100mV – 100mV] [259, 263, 264, 350]
Activators	–	GEA 3162	nifedipine	BTP2 (Agonist) (pEC50 8.1) [‐80mV] [350], decavanadate (Agonist) (pEC50 5.7) [‐100mV] [263]
Gating inhibitors	–	–	2‐APB (Antagonist) Concentration range: 1 × 10−4M [physiological voltage] [410]	flufenamic acid (Antagonist) (pIC50 5.6) [100mV] [366] – Mouse, clotrimazole (Antagonist) Concentration range: 1 × 10−6M‐1 × 10−5M [100mV] [267]
Endogenous channel blockers	Zn2+ (pIC50 6)	Zn2+ (pIC50 6), extracellular H+	Mg2+ (Antagonist) Concentration range: 9 × 10−3M [‐80mV – 80mV] [269] – Mouse, extracellular Na+ (TRPM3α2 only)	–
Channel blockers		2‐APB (Antagonist) (pIC50 6.1) [‐60mV] [361], ACAA (Antagonist) (pIC50 5.8) [physiological voltage] [188], clotrimazole (Antagonist) Concentration range: 3 × 10−6M‐3 × 10−5M [‐60mV – ‐15mV] [131], econazole (Antagonist) Concentration range: 3 × 10−6M‐3 × 10−5M [‐60mV – ‐15mV] [131], flufenamic acid (Antagonist) Concentration range: 5 × 10−5M‐1 × 10−3M [‐60mV – ‐50mV] [130, 361], miconazole (Antagonist) Concentration range: 1 × 10−5M [‐60mV] [361]	Gd3+ (Antagonist) Concentration range: 1 × 10−4M [‐80mV – 80mV] [111, 198], La3+ (Antagonist) Concentration range: 1 × 10−4M [physiological voltage] [111, 198], mefenamic acid [177], pioglitazone (independent of PPAR‐γ) [232], rosiglitazone [232], troglitazone	9‐phenanthrol (pIC50 4.6–4.8) [108], spermine (Antagonist) (pIC50 4.2) [100mV] [265], adenosine (pIC50 3.2)

Nomenclature	TRPM5	TRPM6	TRPM7	TRPM8
HGNC, UniProt	TRPM5, Q9NZQ8	TRPM6, Q9BX84	TRPM7, Q96QT4	TRPM8, Q7Z2W7
EC number	–	2.7.11.1	2.7.11.1	–
Other chemical activators	–	constitutively active, activated by reduction of intracellular Mg2+	activation of PKA	agonist activities are temperature dependent and potentiated by cooling
Physical activators	membrane depolarization (V1/2 = 0 to + 120 mV dependent upon conditions), heat (Q10 = 10.3 @ ‐75 mV between 15 and 25∘C)	–	–	depolarization (V1/2   +50 mV at 15∘C), cooling (< 22‐26∘C)
Functional Characteristics	γ = 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	γ= 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) and ATP	γ = 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+, Sr2+, Zn2+, Mn2+ and Mg.ATP (disputed); activated by and intracellular alkalinization; sensitive to osmotic gradients	γ = 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
Endogenous activators	intracellular Ca2+ (Agonist) (pEC50 4.5–6.2) [‐80mV – 80mV] [139, 217, 366] – Mouse	extracellular H+ (Potentiation), intracellular Mg2+	intracellular ATP (Potentiation), Extracellular H+ (Potentiation), cyclic AMP (elevated cAMP levels)	–
Activators	–	2‐APB (Agonist) (pEC50 3.4–3.7) [‐120mV – 100mV] [207]	2‐APB Concentration range: >1 × 10−3M [249] – Mouse	icilin (Agonist) (pEC50 6.7–6.9) [physiological voltage] [10, 26] – Mouse, (‐)‐menthol (inhibited by intracellular Ca2+) (pEC50 4.6) [‐120mV – 160mV] [371]
Selective activators	–	–	–	WS‐12 (Full agonist) (pEC50 4.9) [physiological voltage] [224, 325] – Rat
Endogenous channel blockers	–	Mg2+ (inward current mediated by monovalent cations is blocked) (pIC50 5.5–6), Ca2+ (inward current mediated by monovalent cations is blocked) (pIC50 5.3–5.3)	–	–
Channel blockers	flufenamic acid (pIC50 4.6), intracellular spermine (pIC50 4.4), Extracellular H+ (pIC50 3.2)	ruthenium red (pIC50 7) [voltage dependent ‐120mV]	spermine (Inhibition) (pK i 5.6) [‐110mV – 80mV] [186] – Rat, 2‐APB (Inhibition) (pIC50 3.8) [‐100mV – 100mV] [207] – Mouse, carvacrol (Inhibition) (pIC50 3.5) [‐100mV – 100mV] [276] – Mouse, Mg2+ (Antagonist) (pIC50 2.5) [80mV] [249] – Mouse, La3+ (Antagonist) Concentration range: 2 × 10−3M [‐100mV – 100mV] [313] – Mouse	BCTC (Antagonist) (pIC50 6.1) [physiological voltage] [26] – Mouse, 2‐APB (Antagonist) (pIC50 4.9–5.1) [100mV – ‐100mV] [141, 254] – Mouse, capsazepine (Antagonist) (pIC50 4.7) [physiological voltage] [26] – Mouse, Δ9‐tetrahydrocannabinol, 5‐benzyloxytryptamine, ACAA, AMTB [196], La3+, NADA, anandamide, cannabidiol, clotrimazole, linoleic acid
Comments	TRPM5 is not blocked by ATP	–	2‐APB acts as a channel blocker in the μM range.	cannabidiol and Δ9‐tetrahydrocannabinol are examples of cannabinoids. TRPM8 is insensitive to ruthenium red. icilin requires intracellular Ca2+ for full agonist activity.

Nomenclature	TRPML1	TRPML2	TRPML3
HGNC, UniProt	MCOLN1, Q9GZU1	MCOLN2, Q8IZK6	MCOLN3, Q8TDD5
Activators	TRPML1Va: Constitutively active, current potentiated by extracellular acidification (equivalent to intralysosomal acidification)	TRPML2Va: Constitutively active, current potentiated by extracellular acidification (equivalent to intralysosomal acidification)	TRPML3Va: Constitutively active, current inhibited by extracellular acidification (equivalent to intralysosomal acidicification) Wild type TRPML3: Activated by Na+‐free extracellular (extracytosolic) solution and membrane depolarization, current inhibited by extracellular acidification (equivalent to intralysosomal acidicification)
Functional Characteristics	TRPML1Va: γ = 40 pS and 76‐86 pS at very negative holding potentials with Fe2+ and monovalent cations as charge carriers, respectively; conducts Na+≈ K+>Cs+ and divalent cations (Ba2+>Mn2+>Fe2+>Ca2+> Mg2+> Ni2+>Co2+> Cd2+>Zn2+≫Cu2+) protons; monovalent cation flux suppressed by divalent cations (e.g. Ca2+, Fe2+); inwardly rectifying	TRPML1Va: Conducts Na+; monovalent cation flux suppressed by divalent cations; inwardly rectifying	TRPML3Va: γ = 49 pS at very negative holding potentials with monovalent cations as charge carrier; conducts Na+> K+> Cs+ with maintained current in the presence of Na+, conducts Ca2+ and Mg2+, but not Fe2+, impermeable to protons; inwardly rectifying Wild type TRPML3: γ = 59 pS at negative holding potentials with monovalent cations as charge carrier; conducts Na+> K+> Cs+ and Ca2+ (PCa/PK≈ 350), slowly inactivates in the continued presence of Na+ within the extracellular (extracytosolic) solution; outwardly rectifying
Channel blockers	–	–	Gd3+ (Antagonist) (pIC50 4.7) [‐80mV] [251] – Mouse

Nomenclature	TRPP1	TRPP2	TRPP3
HGNC, UniProt	PKD2, Q13563	PKD2L1, Q9P0L9	PKD2L2, Q9NZM6
Activators	–	Calmidazolium (in primary cilia): 10 μM	–
Functional Characteristics	The channel properties of TRPP1 (PKD2) have not been determined with certainty	Currents have been measured directly from primary cilia and also when expressed on plasma membranes. Primary cilia appear to contain heteromeric TRPP2 + PKD1‐L1, underlying a gently outwardly rectifying nonselective conductance (PCa/PNa  6: PKD1‐L1 is a 12 TM protein of unknown topology). Primary cilia heteromeric channels have an inward single channel conductance of 80 pS and an outward single channel conductance of 95 pS. Presumed homomeric TRPP2 channels are gently outwardly rectifying. Single channel conductance is 120 pS inward, 200 pS outward [74].	–
Channel blockers	–	phenamil (pIC50 6.9), benzamil (pIC50 6), ethylisopropylamiloride (pIC50 5), amiloride (pIC50 3.8), Gd3+ Concentration range: 1 × 10−4M [‐50mV] [54], La3+ Concentration range: 1 × 10−4M [‐50mV] [54], flufenamate	–

Nomenclature	TRPV1	TRPV2	TRPV3
HGNC, UniProt	TRPV1, Q8NER1	TRPV2, Q9Y5S1	TRPV3, Q8NET8
Other chemical activators	NO‐mediated cysteine S‐nitrosation	–	NO‐mediated cysteine S‐nitrosytion
Physical activators	depolarization (V1/2   0 mV at 35∘C), noxious heat (> 43∘C at pH 7.4)	noxious heat (> 35∘C; rodent, not human) [255]	depolarization (V1/2   +80 mV, reduced to more negative values following heat stimuli), heat (23∘C ‐ 39∘C, temperature threshold reduces with repeated heat challenge)
Functional Characteristics	γ = 35 pS at ‐ 60 mV; 77 pS at + 60 mV, conducts mono and divalent cations with a selectivity for divalents (PCa/PNa = 9.6); 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 Ca2+/ calmodulin; cooling reduces vanilloid‐evoked currents; may be tonically active at body temperature	Conducts mono‐ and divalent 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	γ = 197 pS at = +40 to +80 mV, 48 pS at negative potentials; conducts mono‐ and divalent cations; outward rectification; potentiated by arachidonic acid
Endogenous activators	extracellular H+ (at 37∘C) (pEC50 5.4), 12S‐HPETE (Agonist) (pEC50 5.1) [‐60mV] [145] – Rat, 15S‐HPETE (Agonist) (pEC50 5.1) [‐60mV] [145] – Rat, LTB4 (Agonist) (pEC50 4.9) [‐60mV] [145] – Rat, 5S‐HETE	–	–
Activators	resiniferatoxin (Agonist) (pEC50 8.4) [physiological voltage] [330], capsaicin (Agonist) (pEC50 7.5) [‐100mV – 160mV] [371], camphor, diphenylboronic anhydride, phenylacetylrinvanil [13]	2‐APB (pEC50 5) [255, 301] – Rat, Δ9‐tetrahydrocannabinol (pEC50 4.8) [301] – Rat, cannabidiol (pEC50 4.5) [301], probenecid (pEC50 4.5) [16] – Rat, 2‐APB (Agonist) (pEC50 3.8–3.9) [physiological voltage] [141, 160] – Mouse, diphenylboronic anhydride (Agonist) Concentration range: 1 × 10−4M [‐80mV] [61, 160] – Mouse	incensole acetate (pEC50 4.8) [244] – Mouse, 2‐APB (Full agonist) (pEC50 4.6) [‐80mV – 80mV] [62] – Mouse, diphenylboronic anhydride (Full agonist) (pEC50 4.1–4.2) [voltage dependent ‐80mV – 80mV] [61] – Mouse, (‐)‐menthol (pEC50 1.7) [‐80mV – 80mV] [227] – Mouse, camphor (Full agonist) Concentration range: 1 × 10−3M‐2 × 10−3M [‐60mV] [242] – Mouse, carvacrol (Full agonist) Concentration range: 5 × 10−4M [‐80mV – 80mV] [408] – Mouse, eugenol (Full agonist) Concentration range: 3 × 10−3M [‐80mV – 80mV] [408] – Mouse, thymol (Full agonist) Concentration range: 5 × 10−4M [‐80mV – 80mV] [408] – Mouse
Selective activators	olvanil (Agonist) (pEC50 7.7) [physiological voltage] [330], DkTx (pEC50 6.6) [physiological voltage] [33] – Rat	–	6‐tert‐butyl‐m‐cresol (pEC50 3.4) [374] – Mouse
Channel blockers	5'‐iodoresiniferatoxin (pIC50 8.4), 6‐iodo‐nordihydrocapsaicin (pIC50 8), BCTC (Antagonist) (pIC50 7.5) [52], capsazepine (Antagonist) (pIC50 7.4) [‐60mV] [237], ruthenium red (pIC50 6.7–7), 2‐APB, NADA, allicin, anandamide	ruthenium red (pIC50 6.2), La3+, SKF96365, TRIM (Inhibition) Concentration range: 5 × 10−4M [160] – Mouse, amiloride	diphenyltetrahydrofuran (Antagonist) (pIC50 5–5.2) [‐80mV – 80mV] [61] – Mouse, ruthenium red (Inhibition) Concentration range: 1 × 10−6M [‐60mV] [286] – Mouse
Selective channel blockers	AMG517 (pIC50 9) [31], AMG628 (pIC50 8.4) [383] – Rat, A425619 (pIC50 8.3) [91], A778317 (pIC50 8.3) [28], SB366791 (pIC50 8.2) [119], JYL1421 (Antagonist) (pIC50 8) [388] – Rat, JNJ17203212 (Antagonist) (pIC50 7.8) [physiological voltage] [345], SB705498 (Antagonist) (pIC50 7.1) [118], SB452533	–	–
Labelled ligands	[3H]A778317 (Channel blocker) (pK d 8.5) [28], [125I]resiniferatoxin (Channel blocker, Antagonist) (pIC50 8.4) [‐50mV] [378] – Rat, [3H]resiniferatoxin (Activator)	–	–

Nomenclature	TRPV4	TRPV5	TRPV6
HGNC, UniProt	TRPV4, Q9HBA0	TRPV5, Q9NQA5	TRPV6, Q9H1D0
Activators	–	constitutively active (with strong buffering of intracellular Ca2+)	constitutively active (with strong buffering of intracellular Ca2+)
Other channel blockers	–	Pb2+ = Cu2+ = Gd3+>Cd2+>Zn2+>La3+>Co2+> Fe2	–
Other chemical activators	Epoxyeicosatrieonic acids and NO‐mediated cysteine S‐nitrosylation	–	–
Physical activators	Constitutively active, heat (> 24∘C ‐ 32∘C), mechanical stimuli	–	–
Functional Characteristics	γ =  60 pS at ‐60 mV,  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)	γ = 59‐78 pS for monovalent ions at negative potentials, conducts mono‐ and di‐valents 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 and intracellular acidosis; upregulated by 1,25‐dihydrovitamin D3	γ = 58‐79 pS for monovalent ions at negative potentials, conducts mono‐ and di‐valents 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
Activators	phorbol 12‐myristate 13‐acetate (Agonist) (pEC50 7.9) [physiological voltage] [406]	–	2‐APB (Potentiation)
Selective activators	GSK1016790A (pEC50 8.7) [physiological voltage] [359], 4α‐PDH (pEC50 7.1) [physiological voltage] [176] – Mouse, RN1747 (pEC50 6.1) [physiological voltage] [370], bisandrographolide (Agonist) (pEC50 6) [‐60mV] [333] – Mouse, 4α‐PDD (Agonist) Concentration range: 3 × 10−7M [physiological voltage] [406]	–	–
Channel blockers	Gd3+, La3+, ruthenium red (Inhibition) Concentration range: 1 × 10−6M [physiological voltage] [154], ruthenium red (Inhibition) Concentration range: 2 × 10−7M [physiological voltage] [116] – Rat	ruthenium red (pIC50 6.9), Mg2+, econazole, miconazole	ruthenium red (Antagonist) (pIC50 5) [‐80mV] [136] – Mouse, Cd2+, La3+, Mg2+
Selective channel blockers	HC067047 (Inhibition) (pIC50 7.3) [‐40mV] [93], RN1734 (Inhibition) (pIC50 5.6) [physiological voltage] [370]	–	–

Nomenclature	Cav1.1	Cav1.2	Cav1.3	Cav1.4	Cav2.1
HGNC, UniProt	CACNA1S, Q13698	CACNA1C, Q13936	CACNA1D, Q01668	CACNA1F, O60840	CACNA1A, O00555
Functional Characteristics	L‐type calcium current: High voltage‐activated, slow voltage dependent inactivation	L‐type calcium current: High voltage‐activated, slow voltage‐dependent inactivation, rapid calcium‐dependent inactivation	L‐type calcium current: Voltage‐activated, slow voltage‐dependent inactivation, more rapid calcium‐dependent inactivation	L‐type calcium current: Moderate voltage‐activated, slow voltage‐dependent inactivation	P/Q‐type calcium current: Moderate voltage‐activated, moderate voltage‐dependent inactivation
Activators	(‐)‐(S)‐BayK8644, FPL64176, SZ(+)‐(S)‐202‐791	(‐)‐(S)‐BayK8644, FPL64176 Concentration range: 1 × 10−6M‐5 × 10−6M [219] – Rat, SZ(+)‐(S)‐202‐791	(‐)‐(S)‐BayK8644	(‐)‐(S)‐BayK8644	–
Gating inhibitors	nifedipine (Antagonist)	nifedipine (Antagonist)	nitrendipine (Inhibition) (pIC50 8.4) [329]	–	–
Selective gating inhibitors	–	–	–	–	ω‐agatoxin IVA (P current component: Kd = 2nM, Q component Kd= >100nM) (pIC50 7–8.7) [‐100mV – ‐90mV] [34, 241] – Rat, ω‐agatoxin IVB (pK d 8.5) [‐80mV] [4] – Rat
Channel blockers	diltiazem (Antagonist), verapamil (Antagonist)	diltiazem (Antagonist), verapamil (Antagonist)	verapamil (Antagonist)	–	–
(Sub)family‐selective channel blockers	calciseptine (Antagonist)	calciseptine (Antagonist)	–	–	ω‐conotoxin MVIIC (pIC50 8.2–9.2) Concentration range: 2 × 10−6M‐5 × 10−6M [physiological voltage] [206] – Rat
Comments	–	–	Cav1.3 activates more negative potentials than Cav1.2 and is incompletely inhibited by dihydropyridine antagonists.	Cav1.4 is less sensitive to dihydropyridine antagonists than other Cav1 channels	–

Nomenclature	Cav2.2	Cav2.3	Cav3.1	Cav3.2	Cav3.3
HGNC, UniProt	CACNA1B, Q00975	CACNA1E, Q15878	CACNA1G, O43497	CACNA1H, O95180	CACNA1I, Q9P0X4
Functional Characteristics	N‐type calcium current: High voltage‐activated, moderate voltage‐dependent inactivation	R‐type calcium current: Moderate voltage‐activated, fast voltage‐dependent inactivation	T‐type calcium current: Low voltage‐activated, fast voltage‐dependent inactivation	T‐type calcium current: Low voltage‐activated, fast voltage‐dependent inactivation	T‐type calcium current: Low voltage‐activated, moderate voltage‐dependent inactivation
Gating inhibitors	–	–	kurtoxin (Antagonist) (pIC50 7.3–7.8) [‐90mV] [58, 327] – Rat	kurtoxin (Antagonist) (pIC50 7.3–7.6) [‐90mV] [58, 327] – Rat	–
Selective gating inhibitors	–	SNX482 (Antagonist) (pIC50 7.5–8) [physiological voltage] [256]	–	–	–
Channel blockers	–	Ni2+ (Antagonist) (pIC50 4.6) [‐90mV] [396]	mibefradil (Antagonist) (pIC50 6–6.6) [‐110mV – ‐100mV] [234], Ni2+ (Antagonist) (pIC50 3.6–3.8) [voltage dependent ‐90mV] [197] – Rat	mibefradil (Antagonist) (pIC50 5.9–7.2, median 6.8) [‐110mV – ‐80mV] [234], Ni2+ (Antagonist) (pIC50 4.9–5.2) [voltage dependent ‐90mV] [197]	mibefradil (Antagonist) (pIC50 5.8) [‐110mV] [234], Ni2+ (Antagonist) (pIC50 3.7–4.1) [voltage dependent ‐90mV] [197] – Rat
(Sub)family‐selective channel blockers	ω‐conotoxin GVIA (Antagonist) (pIC50 10.4) [‐80mV] [206] – Rat, ω‐conotoxin MVIIC (Antagonist) (pIC50 6.1–8.5, median 8.2) [‐80mV] [132, 206, 236] – Rat	–	–	–	–

Nomenclature	Hv1
HGNC, UniProt	HVCN1, Q96D96
Functional Characteristics	Activated by membrane depolarization mediating macroscopic currents with time‐, voltage‐ and pH‐dependence; outwardly rectifying; voltage dependent kinetics with relatively slow current activation sensitive to extracellular pH and temperature, relatively fast deactivation; voltage threshold for current activation determined by pH gradient (ΔpH = pHo ‐pHi) across the membrane
Channel blockers	Zn2+ (pIC50∼5.7–6.3), Cd2+ (pIC50∼5)

Nomenclature	Nav1.1	Nav1.2	Nav1.3	Nav1.4	Nav1.5
HGNC, UniProt	SCN1A, P35498	SCN2A, Q99250	SCN3A, Q9NY46	SCN4A, P35499	SCN5A, Q14524
Functional Characteristics	Activation V0.5 = ‐20 mV. Fast inactivation (τ = 0.7 ms for peak sodium current).	Activation V0.5 = ‐24 mV. Fast inactivation (τ = 0.8 ms for peak sodium current).	Activation V0.5 = ‐24 mV. Fast inactivation (0.8 ms)	Activation V0.5 = ‐30 mV. Fast inactivation (0.6 ms)	Activation V0.5 = ‐26 mV. Fast inactivation (τ = 1 ms for peak sodium current).
(Sub)family‐selective activators	batrachotoxin, veratridine	batrachotoxin (Agonist) (pK d 9.1) [physiological voltage] [213] – Rat, veratridine (Partial agonist) (pK d 5.2) [physiological voltage] [49] – Rat	batrachotoxin, veratridine	batrachotoxin (Full agonist) Concentration range: 5 × 10−6M [‐100mV] [386] – Rat, veratridine (Partial agonist) Concentration range: 2 × 10−4M [‐100mV] [386] – Rat	batrachotoxin (Full agonist) (pK d 7.6) [physiological voltage] [324] – Rat, veratridine (Partial agonist) (pEC50 6.3) [‐30mV] [381] – Rat
(Sub)family‐selective channel blockers	saxitoxin (Pore blocker), tetrodotoxin (Pore blocker) Concentration range: 1 × 10−8M	saxitoxin (Pore blocker) (pIC50 8.8) [‐120mV] [36] – Rat, tetrodotoxin (Pore blocker) (pIC50 8) [‐120mV] [36] – Rat, lacosamide (Antagonist) (pIC50 4.5) [‐80mV] [1] – Rat	tetrodotoxin (Pore blocker) (pIC50 8.4) [55], saxitoxin (Pore blocker)	saxitoxin (Pore blocker) (pIC50 8.4) [‐100mV] [288] – Rat, tetrodotoxin (Pore blocker) (pIC50 7.6) [‐120mV] [51], μ‐conotoxin GIIIA (Pore blocker) (pIC50 5.9) [‐100mV] [51]	tetrodotoxin (Pore blocker) (pK d 5.8) [‐80mV] [69, 418] – Rat

Nomenclature	Nav1.6	Nav1.7	Nav1.8	Nav1.9
HGNC, UniProt	SCN8A, Q9UQD0	SCN9A, Q15858	SCN10A, Q9Y5Y9	SCN11A, Q9UI33
Functional Characteristics	Activation V0.5 = ‐29 mV. Fast inactivation (1 ms)	Activation V0.5 = ‐27 mV. Fast inactivation (0.5 ms)	Activation V0.5 = ‐16 mV. Inactivation (6 ms)	Activation V0.5 = ‐32 mV. Slow inactivation (16 ms)
(Sub)family‐selective activators	batrachotoxin, veratridine	batrachotoxin, veratridine	–	–
(Sub)family‐selective channel blockers	tetrodotoxin (Pore blocker) (pIC50 9) [‐130mV] [83] – Rat, saxitoxin (Pore blocker)	tetrodotoxin (Pore blocker) (pIC50 7.6) [‐100mV] [178], saxitoxin (Pore blocker) (pIC50 6.2) [379]	tetrodotoxin (Pore blocker) (pIC50 4.2) [‐60mV] [5] – Rat	tetrodotoxin (Pore blocker) (pIC50 4.4) [‐120mV] [70] – Rat
Selective channel blockers	–	–	PF‐01247324 (Pore blocker) (pIC50 6.7) [voltage dependent] [281]	–