THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Voltage‐gated ion channels

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

2S161 CatSper and Two‐Pore channels

3S162 Cyclic nucleotide‐regulated channels

4S164 Potassium channels

5S165 Calcium‐ and sodium‐activated potassium channels

6S166 Inwardly rectifying potassium channels

7S169 Two P domain potassium channels

8S171 Voltage‐gated potassium channels

9S175 Ryanodine receptors

10S176 Transient Receptor Potential channels

11S186 Voltage‐gated calcium channels

12S188 Voltage‐gated proton channel

13S189 Voltage‐gated sodium channels

14CatSper channels (CatSper1‐4, nomenclature as agreed by NC‐IUPHAR [ 69 ]) 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[193]. In mammals, CatSper subunits are structurally most closely related to individual domains of voltage‐activated calcium channels (Cav) [349]. CatSper1 [349], CatSper2 [341] and CatSpers 3 and 4 [173, 245, 338], in common with a putative 2TM auxiliary CatSperβ protein [242] and two putative 1TM associated CatSperγ and CatSperδ proteins [64, 434], are restricted to the testis and localised to the principle piece of sperm tail.

15Two‐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 [43]. TPC3 is also found on the plasma membrane and forms a voltage‐activated, non‐inactivating Na+ channel [44]. All the three TPCs are Na+‐selective under whole‐cell or whole‐organelle patch clamp recording [45, 46, 457]. The channels may also conduct Ca2+[272].

16CatSper channel subunits expressed singly, or in combination, fail to functionally express in heterologous expression systems [341, 349]. 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 [193] and also mature human sperm [239, 390]. 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[64, 242, 338]. 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 [51, 64, 338]. Thus, it is likely that the CatSper pore is formed by a heterotetramer of CatSpers1‐4 [338] in association with the auxiliary subunits (β, γ, δ) that are also essential for function [64]. CatSper channels are required for the increase in intracellular Ca2+ concentration in sperm evoked by egg zona pellucida glycoproteins [457]. Mouse and human sperm swim against the fluid flow and Ca2+ signaling through CatSper is required for the rheotaxis [268]. In vivo, CatSper1‐null spermatozoa cannot ascend the female reproductive tracts efficiently [65, 151]. It has been shown that CatSper channels form four linear Ca2+ signaling domains along the flagella, which orchestrate capacitation‐associated tyrosine phosphorylation [65].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 [283]. Mouse KSper is encoded by mSlo3, a protein detected only in testis [262, 283, 478]. In human sperm, such alkalinization may result from the activation of Hv1, a proton channel [240]. Mutations in CatSpers are associated with syndromic and non‐syndromic male infertility [144]. In human ejaculated spermatozoa, progesterone (<50 nM) potentiates the CatSper current by a non‐genomic mechanism and acts synergistically with intracellular alkalinisation [239, 390]. Sperm cells from infertile patients with a deletion in CatSper2 gene lack ICatSper and the progesterone response [375]. In addition, certain prostaglandins (e.g. PGF1α, PGE1) also potentiate CatSper mediated currents [239, 390].

17In human sperm, CatSper channels are also activated by various small molecules including endocrine disrupting chemicals (EDC) and proposed as a polymodal sensor [39, 39].

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 [45], PI(3,5)P2 [439], intracellular ATP and extracellular amino acids [46]. TPCs are also involved in the NAADP‐activated Ca2+ release from lysosomal Ca2+ stores [43, 272]. Mice lacking TPCs are viable but have phenotypes including compromised lysosomal pH stability, reduced physical endurance [46], resistance to Ebola viral infection [358] and fatty liver [124]. No major human disease‐associated TPC mutation has been reported.

19Clapham 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]

20Grimm C et al. (2017) Two‐Pore Channels: Catalyzers of Endolysosomal Transport and Function. Front Pharmacol 8: 45 [PMID:28223936]

21Kintzer AF et al. (2017) On the Structure and Mechanism of Two‐Pore Channels. FEBS J [PMID:28656706]

22Cyclic 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 [ 154 ].

23CNG 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 [107, 188], 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 [282] and the pineal gland [95]. 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.

24CNGA1, 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 [323, 445, 480, 481, 483].

25The 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 [92, 308]. In native cells, these currents have a variety of names, such as Ih, Iq andIf. 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 [ 154 ].

26HCN 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[37] and ivabradine[42] have proven useful in identifying and studying functional HCN channels in native cells. Zatebradine and cilobradine are also useful blocking agents.

27Herrmann S et al. (2015) HCN channels–modulators of cardiac and neuronal excitability. Int J Mol Sci 16: 1429‐47 [PMID:25580535]

28Hofmann 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]

29Podda MV et al. (2014) New perspectives in cyclic nucleotide‐mediated functions in the CNS: the emerging role of cyclic nucleotide‐gated (CNG) channels. Pflugers Arch 466: 1241‐57 [PMID:24142069]

30Tsantoulas C et al. (2016) HCN2 ion channels: basic science opens up possibilities for therapeutic intervention in neuropathic pain. Biochem J 473: 2717‐36 [PMID:27621481]

31Activation of potassium channels regulates excitability and can control the shape of the action potential waveform. They are present in all cells within the body and can influence processes as diverse as cognition, muscle contraction and hormone secretion. Potassium channels are subdivided into families, based on their structural and functional properties. The largest family consists of potassium channels that activated by membrane depolarization, with other families consisting of channels that are either activated by a rise of intracellular calcium ions or are constitutively active. A standardised nomenclature for potassium channels has been proposed by the NC‐IUPHAR subcommittees on potassium channels [120, 135, 211, 444], which has placed cloned channels into groups based on gene family and structure of channels that exhibit 6, 4 or 2 transmembrane domains (TM).

32The 6TM family of K channels comprises the voltage‐gated KVsubfamilies, including the KCNQ subfamily, the EAG subfamily (which includes herg channels), the Ca2+‐activated Slo subfamily (actually with 6 or 7TM) and the Ca2+‐ and Na+‐activated SK subfamily (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Calcium‐ and sodium‐activated potassium channels [ 181 ]). 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).

33The 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) that are constitutively active, the G‐protein‐activated inward‐rectifier K channels (Kir3.x) and the ATP‐sensitive K channels (Kir6.x, which combine with sulphonylurea receptors (SUR1‐3)). The pore‐forming α subunits form tetramers, and heteromeric channels may be formed within subfamilies (e.g. Kir3.2 with Kir3.3).

34The 4TM family of K channels mediate many of the background potassium currents observed in native cells. They are open across the physiological voltage‐range and are regulated by a wide array of neurotransmitters and biochemical mediators. The pore‐forming α‐subunit contains two pore loop (P) domains and two subunits assemble to form one ion conduction pathway lined by four P domains. It is important to note that single channels do not have two pores but that each subunit has two P domains in its primary sequence; hence the name two P domain, or K2P channels (and not two‐pore channels). Some of the K2P subunits can form heterodimers across subfamilies (e.g. K2P3.1 with K2P9.1). The nomenclature of 4TM K channels in the literature is still a mixture of IUPHAR and common names. The suggested division into subfamilies, below, is based on similarities in both structural and functional properties within subfamilies.

35The K2P6, 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.

36The 6TM family of K channels comprises the voltage‐gated KVsubfamilies, the EAG subfamily (which includes hERG channels), the Ca2+‐activated Slo subfamily (actually with 7TM, termed BK) and the Ca2+‐activated SK subfamily. These channels possess a pore‐forming α subunit that comprise tetramers of identical subunits (homomeric) or of different subunits (heteromeric). Heteromeric channels can only be formed within subfamilies (e.g. Kv1.1 with Kv1.2; Kv7.2 with Kv7.3). The pharmacology largely reflects the subunit composition of the functional channel.

37Chang PC et al. (2015) SK channels and ventricular arrhythmias in heart failure. Trends Cardiovasc Med 25: 508‐14 [PMID:25743622]

38Decher N et al. (2017) Stretch‐activated potassium currents in the heart: Focus on TREK‐1 and arrhythmias. Prog Biophys Mol Biol [PMID:28526352]

39Feliciangeli S et al. (2015) The family of K2P channels: salient structural and functional properties. J Physiol 593: 2587‐603 [PMID:25530075]

40Foster MN et al. (2016) KATP Channels in the Cardiovascular System. Physiol Rev 96: 177‐252 [PMID:26660852]

41Goldstein 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]

42Greene DL et al. (2017) Modulation of Kv7 channels and excitability in the brain. Cell Mol Life Sci 74: 495‐508 [PMID:27645822]

43Gutman GA et al. (2003) International Union of Pharmacology. XLI. Compendium of voltage‐gated ion channels: potassium channels. Pharmacol Rev 55: 583‐6 [PMID:14657415]

44Kaczmarek LK et al. (2017) International Union of Basic and Clinical Pharmacology. C. Nomenclature and Properties of Calcium‐Activated and Sodium‐Activated Potassium Channels. Pharmacol Rev 69: 1‐11 [PMID:28267675]

45Kubo 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]

46Latorre R et al. (2017) Molecular Determinants of BK Channel Functional Diversity and Functioning. Physiol Rev 97: 39‐87 [PMID:27807200]

47Niemeyer MI et al. (2016) Gating, Regulation, and Structure in K2P K+ Channels: In Varietate Concordia? Mol Pharmacol 90: 309‐17 [PMID:27268784]

48Poveda JA et al. (2017) Towards understanding the molecular basis of ion channel modulation by lipids: Mechanistic models and current paradigms. Biochim Biophys Acta 1859: 1507‐1516 [PMID:28408206]

49Rifkin RA et al. (2017) G Protein‐Gated Potassium Channels: A Link to Drug Addiction. Trends Pharmacol Sci 38: 378‐392 [PMID:28188005]

50Taylor KC et al. (2017) Regulation of KCNQ/Kv7 family voltage‐gated K+ channels by lipids. Biochim Biophys Acta 1859: 586‐597 [PMID:27818172]

51Vivier D et al. (2016) Perspectives on the Two‐Pore Domain Potassium Channel TREK‐1 (TWIK‐Related K(+) Channel 1). A Novel Therapeutic Target? J Med Chem 59: 5149‐57 [PMID:26588045]

52Wei 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]

53Yang KC et al. (2016) Mechanisms contributing to myocardial potassium channel diversity, regulation and remodeling. Trends Cardiovasc Med 26: 209‐18 [PMID:26391345]

54Grissmer M et al. (2005) International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage‐gated potassium channels. Pharmacol Rev 57: 473‐508 [PMID:16382104]

55The ryanodine receptors (RyRs) are found on intracellular Ca2+ storage/release organelles. The family of RyR genes encodes three highly related Ca2+ release channels: RyR1, RyR2 and RyR3, which assemble as large tetrameric structures. These RyR channels are ubiquitously expressed in many types of cells and participate in a variety of important Ca2+ signaling phenomena (neurotransmission, secretion, etc.). In addition to the three mammalian isoforms described below, various nonmammalian isoforms of the ryanodine receptor have been identified [392]. The function of the ryanodine receptor channels may also be influenced by closely associated proteins such as the tacrolimus (FK506)‐binding protein, calmodulin [467], triadin, calsequestrin, junctin and sorcin, and by protein kinases and phosphatases.

56The modulators of channel function included in this table are those most commonly used to identify ryanodine‐sensitive Ca2+ release pathways. Numerous other modulators of ryanodine receptor/channel function can be found in the reviews listed below. The absence of a modulator of a particular isoform of receptor indicates that the action of that modulator has not been determined, not that it is without effect. The potential role of cyclic ADP ribose as an endogenous regulator of ryanodine receptor channels is controversial. A region of RyR likely to be involved in ion translocation and selection has been identified [112, 479].

57O'Brien F et al. (2015) The ryanodine receptor provides high throughput Ca2+‐release but is precisely regulated by networks of associated proteins: a focus on proteins relevant to phosphorylation. Biochem Soc Trans 43: 426‐33 [PMID:26009186]

58Samso M. (2017) A guide to the 3D structure of the ryanodine receptor type 1 by cryoEM. Protein Sci 26: 52‐68 [PMID:27671094]

59Van Petegem F. (2015) Ryanodine receptors: allosteric ion channel giants. J Mol Biol 427: 31‐53 [PMID:25134758]

60Zalk R et al. (2017) Ca2+ Release Channels Join the 'Resolution Revolution'. Trends Biochem Sci 42: 543‐555 [PMID:28499500]

61The TRP superfamily of channels (nomenclature as agreed by NC‐IUPHAR [ 70, 455 ]), 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 [307]). 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 [168]. The established, or potential, involvement of TRP channels in disease is reviewed in [196, 288] and [290], together with a special edition of Biochemica et Biophysica Acta on the subject [288]. The pharmacology of most TRP channels is poorly developed [455]. 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 [291, 353, 424]). 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.

62TRPA1 is the sole mammalian member of this group (reviewed by [114]). TRPA1 activation of sensory neurons contribute to nociception [177, 266, 386]. 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 [22, 149, 251, 253]. 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 [11, 22]. Covalent modification leads to sustained activation of TRPA1. Chemicals including carvacrol, menthol, and local anesthetics reversibly activate TRPA1 by non‐covalent binding [186, 222, 460, 461]. TRPA1 is not mechanosensitive under physiological conditions, but can be activated by cold temperatures [86, 187]. The electron cryo‐EM structure of TRPA1 [315] 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.

63Members of the TRPC subfamily (reviewed by [2, 8, 27, 31, 111, 194, 312, 337]) fall into the subgroups outlined below. TRPC2 is a pseudogene in humans. It is generally accepted that all TRPC channels are activated downstream of Gq/11‐coupled receptors, or receptor tyrosine kinases (reviewed by [333, 415, 455]). 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 [195]. 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, 61, 321, 334, 359, 475]). 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[139, 140]. Activation of TRPC channels by lipids is discussed by [27].

64TRPC4/C5 may be distinguished from other TRP channels by their potentiation by micromolar concentrations of La3+. TRPC2 is a pseudogene in humans, but in other mammals appears to be an ion channel localized to microvilli of the vomeronasal organ. It is required for normal sexual behavior in response to pheromones in mice. It may also function in the main olfactory epithelia in mice [236, 304, 305, 472, 473, 474, 487].

65All members are activated by diacylglycerol independent of protein kinase C stimulation [140].

66Members of the TRPM subfamily (reviewed by [109, 139, 321, 482]) fall into the five subgroups outlined below.

67In darkness, glutamate released by the photoreceptors and ON‐bipolar cells binds to the metabotropic glutamate receptor 6, leading to activation of Go. This results in the closure of TRPM1. When the photoreceptors are stimulated by light, glutamate release is reduced, and TRPM1 channels are more active, resulting in cell membrane depolarization. Human TRPM1 mutations are associated with congenital stationary night blindness (CSNB), whose patients lack rod function. TRPM1 is also found melanocytes. Isoforms of TRPM1 may present in melanocytes, melanoma, brain, and retina. In melanoma cells, TRPM1 is prevalent in highly dynamic intracellular vesicular structures [165, 298].TRPM3 (reviewed by [301]) 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 is expressed in somatosensory neurons and may be important in development of heat hyperalgesia during inflammation. TRPM3 is frequently coexpressed with TRPA1 and TRPV1 in these neurons. TRPM3 is expressed in pancreatic beta cells as well as brain, pituitary gland, eye, kidney, and adipose tissue [300, 408]. TRPM3 may contribute to the detection of noxious heat [428].

68TRPM2 is activated under conditions of oxidative stress (respiratory burst of phagocytic cells) and ischemic conditions. However, the direct activators are ADPR(P) and calcium. As for many ion channels, PIP2 must also be present (reviewed by [468]). Numerous splice variants of TRPM2 exist which differ in their activation mechanisms [96]. 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) [417].

69TRPM4 and TRPM5 have the distinction within all TRP channels of being impermeable to Ca2+[455]. A splice variant of TRPM4 (i.e.TRPM4b) and TRPM5 are molecular candidates for endogenous calcium‐activated cation (CAN) channels [130]. TRPM4 is active in the late phase of repolarization of the cardiac ventricular action potential. TRPM4 enhances beta adrenergic‐mediated inotropy. Mutations are associated with conduction defects [170, 263, 381]. TRPM4 has been shown to be an important regulator of Ca2+ entry in to mast cells [420] and dendritic cell migration [17]. TRPM5 in taste receptor cells of the tongue appears essential for the transduction of sweet, amino acid and bitter stimuli [235] TRPM5 contributes to the slow afterdepolarization of layer 5 neurons in mouse prefrontal cortex [223].

70TRPM6 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.

71Is a channel activated by cooling and pharmacological agents evoking a ‘cool’ sensation and participates in the thermosensation of cold temperatures [24, 71, 90] reviewed by [200, 244, 277, 425].

72The TRPML family [75, 336, 339, 463, 476] 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. TRPML2 and TRPML3 show increased channel activity in low extracellular sodium and are activated by similar small molecules [125]. 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 [292, 339]).

73The TRPP family (reviewed by [87, 89, 118, 153, 451]) or PKD2 family is comprised of PKD2, PKD2L1 and PKD2L2, which have been renamed TRPP1, TRPP2 and TRPP3, respectively [455]. 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.

74Members of the TRPV family (reviewed by [421]) can broadly be divided into the non‐selective cation channels, TRPV1‐4 and the more calcium selective channels TRPV5 and TRPV6.

75TRPV1 is involved in the development of thermal hyperalgesia following inflammation and may contribute to the detection of noxius heat (reviewed by [330, 382, 395]). 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 [366]. The pharmacology of TRPV1 channels is discussed in detail in [132] and [427]. TRPV2 is probably not a thermosensor in man [309], but has recently been implicated in innate immunity [238]. 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 [47, 232].

76Under 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 [81, 104, 278, 449]).

77Agents activating TRPA1 in a covalent manner are thiol reactive electrophiles that bind to cysteine and lysine residues within the cytoplasmic domain of the channel [149, 250]. 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 [16]. In addition, TRPA1 is potently activated by intracellular zinc (EC50= 8 nM) [10, 156].

78Ca2+ activates all splice variants of TRPM2, but other activators listed are effective only at the full length isoform [96]. 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 [418]. The V½ 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 V½ is shifted in the hyperpolarizing direction both by decreasing temperature and by exogenous agonists, such as (‐)‐menthol[423] whereas antagonists produce depolarizing shifts in V½[276]. The V½ for the native channel is far more positive than that of heterologously expressed TRPM8 [276]. It should be noted that (‐)‐menthol and structurally related compounds can elicit release of Ca2+ from the endoplasmic reticulum independent of activation of TRPM8 [254]. Intracellular pH modulates activation of TRPM8 by cold and icilin, but not (‐)‐menthol[9].

79Data 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 [94, 123, 191, 281, 462]. Data for wild type TRPML3 are also tabulated [191, 192, 281, 462]. It should be noted that alternative methodologies, particularly in the case of TRPML1, have resulted in channels with differing biophysical characteristics (reviewed by [336]).

80Data in the table are extracted from [79, 89] and [370]. Broadly similar single channel conductance, mono‐ and di‐valent cation selectivity and sensitivity to blockers are observed for TRPP2 co‐expressed with TRPP1 [88]. 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.

81Activation of TRPV1 by depolarisation is strongly temperature‐dependent via a channel opening rate that increases with increasing temperature. The V½ is shifted in the hyperpolarizing direction both by increasing temperature and by exogenous agonists [423]. 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 [296]). 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.

82Aghazadeh Tabrizi M et al. (2017) Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists. Med Res Rev 37: 936‐983 [PMID:27976413]

83Basso L et al. (2017) Transient Receptor Potential Channels in neuropathic pain. Curr Opin Pharmacol 32: 9‐15 [PMID:27835802]

84Ciardo MG et al. (2017) Lipids as central modulators of sensory TRP channels. Biochim Biophys Acta 1859: 1615‐1628 [PMID:28432033]

85Clapham 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]

86Diaz‐Franulic I et al. (2016) Allosterism and Structure in Thermally Activated Transient Receptor Potential Channels. Annu Rev Biophys 45: 371‐98 [PMID:27297398]

87Grace MS et al. (2017) Modulation of the TRPV4 ion channel as a therapeutic target for disease. Pharmacol Ther [PMID:28202366]

88Grayson TH et al. (2017) Transient receptor potential canonical type 3 channels: Interactions, role and relevance ‐ A vascular focus. Pharmacol Ther 174: 79‐96 [PMID:28223224]

89Kashio M et al. (2017) The TRPM2 channel: a thermo‐sensitive metabolic sensor. Channels (Austin) 0 [PMID:28633002]

90Wu 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]

91Zierler S et al. (2017) TRPM channels as potential therapeutic targets against pro‐inflammatory diseases. Cell Calcium [PMID:28549569]

92Calcium (Ca2+) channels are voltage‐gated ion channels present in the membrane of most excitable cells. The nomenclature for Ca2+channels was proposed by [101] and approved by the NC‐IUPHAR Subcommittee on Ca2+ channels [ 54 ]. 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.

93In 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 [447].

94Catterall WA et al. (2015) Structural Basis for Pharmacology of Voltage‐Gated Sodium and Calcium Channels. Mol Pharmacol 88: 141‐50 [PMID:25848093]

95Catterall WA et al. (2005) International Union of Pharmacology. XLVIII. Nomenclature and structure‐function relationships of voltage‐gated calcium channels. Pharmacol Rev 57: 411‐25 [PMID:16382099]

96Catterall WA et al. (2015) Deciphering voltage‐gated Na(+) and Ca(2+) channels by studying prokaryotic ancestors. Trends Biochem Sci 40: 526‐34 [PMID:26254514]

97Dolphin AC. (2016) Voltage‐gated calcium channels and their auxiliary subunits: physiology and pathophysiology and pharmacology. J Physiol 594: 5369‐90 [PMID:27273705]

98Huang J et al. (2017) Regulation of voltage gated calcium channels by GPCRs and post‐translational modification. Curr Opin Pharmacol 32: 1‐8 [PMID:27768908]

99Ortner NJ et al. (2016) L‐type calcium channels as drug targets in CNS disorders. Channels (Austin) 10: 7‐13 [PMID:26039257]

100Rougier JS et al. (2016) Cardiac voltage‐gated calcium channel macromolecular complexes. Biochim Biophys Acta 1863: 1806‐12 [PMID:26707467]

101Zamponi GW. (2016) Targeting voltage‐gated calcium channels in neurological and psychiatric diseases. Nat Rev Drug Discov 15: 19‐34 [PMID:26542451]

102The 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 [49, 84, 85, 346, 362]. 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 [346, 362]. 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 [345, 453]. Hv1 expresses largely as a dimer mediated by intracellular C‐terminal coiled‐coil interactions [231] but individual promoters nonetheless support gated H+ flux via separate conduction pathways [203, 221, 327, 412]. 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 [121, 413].

103The 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 [49, 84, 85]. Phosphorylation of Hv1 within the N‐terminal domain by PKC enhances the gating of the channel [274]. Tabulated IC50 values for Zn2+ and Cd2+ are for heterologously expressed human and mouse Hv1 [346, 362]. Zn2+ is not a conventional pore blocker, but is coordinated by two, or more, external protonation sites involving histamine residues [346]. Zn2+ binding may occur at the dimer interface between pairs of histamine residues from both monomers where it may interfere with channel opening [275]. 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 [347]. Additional physiological functions of Hv1 are reviewed by [49].

104Castillo K et al. (2015) Voltage‐gated proton (H(v)1) channels, a singular voltage sensing domain. FEBS Lett 589: 3471‐8 [PMID:26296320]

105DeCoursey TE. (2015) The Voltage‐Gated Proton Channel: A Riddle, Wrapped in a Mystery, inside an Enigma. Biochemistry 54: 3250‐68 [PMID:25964989]

106DeCoursey TE. (2013) Voltage‐gated proton channels: molecular biology, physiology, and pathophysiology of the H(V) family. Physiol Rev 93: 599‐652 [PMID:23589829]

107Fernandez A et al. (2016) Pharmacological Modulation of Proton Channel Hv1 in Cancer Therapy: Future Perspectives. Mol Pharmacol 90: 385‐402 [PMID:27260771]

108Okamura Y et al. (2015) Gating mechanisms of voltage‐gated proton channels. Annu Rev Biochem 84: 685‐709 [PMID:26034892]

109Sodium 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 [169]. 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 [316]. 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 [316]. Auxiliary β1, β2, β3 and β4 subunits consist of a large extracellular N‐terminal domain, a single transmembrane segment and a shorter cytoplasmic domain.

110The nomenclature for sodium channels was proposed by Goldin et al., (2000) [ 119 ] and approved by the NC‐IUPHAR Subcommittee on sodium channels (Catterall et al., 2005, [ 52 ]).

111Sodium 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.

112Catterall WA et al. (2005) International Union of Pharmacology. XLVII. Nomenclature and structure‐function relationships of voltage‐gated sodium channels. Pharmacol Rev 57: 397‐409 [PMID:16382098]

113Catterall WA et al. (2017) The chemical basis for electrical signaling. Nat Chem Biol 13: 455‐463 [PMID:28406893]

114Deuis JR et al. (2017) The pharmacology of voltage‐gated sodium channel activators. Neuropharmacology [PMID:28416444]

115Kanellopoulos AH et al. (2016) Voltage‐gated sodium channels and pain‐related disorders. Clin Sci (Lond) 130: 2257‐2265 [PMID:27815510]

116Terragni B et al. (2017) Post‐translational dysfunctions in channelopathies of the nervous system. Neuropharmacology [PMID:28571716]