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

The Concise Guide to PHARMACOLOGY 2017/18 provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), 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. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13884/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 landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2017, and supersedes data presented in the 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature Committee of the Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.


Voltage-gated ion channels → CatSper and Two-Pore channels
Overview: CatSper 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 I CatSper [193]. In mammals, CatSper subunits are structurally most closely related to individual domains of voltage-activated calcium channels (Ca v ) [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. Two-pore channels (TPCs) are structurally related to CatSpers, Ca V s and Na V s. TPCs have a 2x6TM structure with twice the number of TMs of CatSpers and half that of Ca V s. There are three an-imal 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 Ca 2+ [272].
Activators CatSper1 is constitutively active, weakly facilitated by membrane depolarisation, strongly augmented by intracellular alkalinisation. In human, but not mouse, spermatozoa progesterone (EC 50˜8 nM) also potentiates the CatSper current (I CatSper ) [239,390] ---Channel blockers ruthenium red (pIC 50 5) [193] -Mouse, HC-056456 (pIC 50 4.7) [50], Cd 2+ (pIC 50 3.7) [193] -Mouse, Ni 2+ (pIC 50  Calcium selective ion channel (Ba 2+ >Ca 2+ Mg 2+ Na + ); quasilinear monovalent cation current in the absence of extracellular divalent cations; alkalinization shifts the voltage-dependence of activation towards negative potentials [V ½ @ pH 6.0 = +87 mV (mouse); V ½ @ pH 7.5 = +11mV (mouse) or pH 7.4 = +85 mV (human)]; required for I CatSper and male fertility (mouse and human) Required for I CatSper and male fertility (mouse and human) Required for I CatSper and male fertility (mouse) Required for I CatSper and male fertility (mouse) are required for the increase in intracellular Ca 2+ concentration in sperm evoked by egg zona pellucida glycoproteins [457]. Mouse and human sperm swim against the fluid flow and Ca 2+ 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 Ca 2+ signaling domains along the flagella, which orchestrate capacitation-associated tyrosine phosphorylation [65].The driving force for Ca 2+ 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 H v 1, a proton channel [240]. Mutations in CatSpers are associated with syndromic and nonsyndromic 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 I CatSper and the progesterone response [375]. In addition, certain prostaglandins (e.g. PGF 1α , PGE 1 ) also potentiate CatSper mediated currents [239,390]. In human sperm, CatSper channels are also activated by various small molecules including endocrine disrupting chemicals (EDC) and proposed as a polymodal sensor [39,39]. 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 [45], PI(3,5)P2 [439], intracellular ATP and extracellular amino acids [46]. TPCs are also involved in the NAADP-activated Ca 2+ release from lysosomal Ca 2+ 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.

Cyclic nucleotide-regulated channels
Voltage-gated ion channels → Cyclic nucleotide-regulated channels Overview: Cyclic nucleotide-gated (CNG) channels are responsible for signalling in the primary sensory cells of the vertebrate visual and olfactory systems. A standardised nomenclature for CNG channels has been proposed by the NC-IUPHAR subcommittee on voltage-gated ion channels [154]. 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 [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.  [355], L-(cis)-diltiazem (high affinity binding requires presence of CNGB subunits) (pK i 4) [-80mV -80mV] [58] dequalinium (pIC 50 5.6) [0mV] [354] -L-(cis)-diltiazem (Channel blocker when CNGB3 coexpressed with CNGA3) (pIC 50

Hyperpolarisation-activated, cyclic nucleotide-gated (HCN) channels
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 [92,308]. In native cells, these currents have a variety of names, such as I h , I q andI f . The four known HCN channels have six transmembrane domains and form tetramers.
It is believed that the channels can form heteromers with each other, as has been shown for HCN1 and HCN4 [7]. A standardised nomenclature for HCN channels has been proposed by the NC-IUPHAR subcommittee on voltage-gated ion channels [154].

Potassium channels
Voltage-gated ion channels → Potassium channels Overview: Activation 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). Two P domain potassium channels Voltage-gated ion channels → Potassium channels → Two P domain potassium channels Overview: The 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 K 2P channels (and not two-pore channels). Some of the K 2P subunits can form heterodimers across subfamilies (e.g. K 2P 3.1 with K 2P 9.1). 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. arachidonic acid (studied at 1-10 μM) [108] Activators -chloroform (studied at 1-5 mM) Concentration range: 8×10 −3 M [313], halothane (studied at 1-5 mM) [313], isoflurane (studied at 1-5 mM) [313] halothane (studied at 1-10 mM) riluzole (studied at 1-100 μM) [97] Channel blockers --  [331]. K 2P 1 forms heterodimers with K 2P 3 and K 2P 9 [332]. K 2P 2.1 is also activated by membrane stretch, heat and acid pH i [256,258]. K 2P 2 can heterodimerize with K 2P 4 [33] and K 2P 10 [228].
-K 2P 16.1 current is increased by alkaline pH o with a pK a of 7.8 [184].
K 2P 17.1 current is increased by alkaline pH o with a pK a of 8.8 [184].
A frame-shift mutation (F139WfsX24) in the KCNK18 gene, is associated with migraine with aura in humans [214].

Comments:
The K 2P 6, K 2P 7.1, K 2P 15.1 and K 2P 12.1 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 Ba 2+ ions.

Voltage-gated potassium channels
Voltage-gated ion channels → Potassium channels → Voltage-gated potassium channels Overview: The 6TM family of K channels comprises the voltage-gated K V subfamilies, the EAG subfamily (which includes hERG channels), the Ca 2+ -activated Slo subfamily (actually with 7TM, termed BK) and the Ca 2+ -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. K v 1.1 with K v 1.2; K v 7.2 with K v 7.3). The pharmacology largely reflects the subunit composition of the functional channel.

Ryanodine receptors
Voltage-gated ion channels → Ryanodine receptors Overview: The ryanodine receptors (RyRs) are found on intracellular Ca 2+ storage/release organelles. The family of RyR genes encodes three highly related Ca 2+ 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 Ca 2+ 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 func-tion 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. ). 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 [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 Ca 2+ 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 [2,8,27,31,111,194,312,337]) fall into the subgroups outlined below. TRPC2 is a pseudogene in humans. It is generally accepted that all TRPC channels are activated downstream of G q/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]. TRPC1/C4/C5 subgroup TRPC4/C5 may be distinguished from other TRP channels by their potentiation by micromolar concentrations of La 3+ . 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]. TRPC3/C6/C7 subgroup All members are activated by diacylglycerol independent of protein kinase C stimulation [140].

TRPM1/M3 subgroup
In darkness, glutamate released by the photoreceptors and ONbipolar 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 hTRPM3 1325 ) 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]. TRPM2 TRPM2 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, PIP 2 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]. TRPM4/5 subgroup TRPM4 and TRPM5 have the distinction within all TRP channels of being impermeable to Ca 2+ [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 Ca 2+ 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]. TRPM6/7 subgroup TRPM6 and 7 combine channel and enzymatic activities ('chanzymes'). These channels have the unusual property of permeation by divalent (Ca 2+ , Mg 2+ , Zn 2+ ) and monovalent cations, high single channel conductances, but overall extremely small inward conductance when expressed to the plasma membrane. They are inhibited by internal Mg 2+ at˜0.6 mM, around the free level of Mg 2+ in cells. Whether they contribute to Mg 2+ 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 [24,71,90] reviewed by [200,244,277,425].
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] conducts Na + > K + > Cs + and Ca 2+ (P Ca /P K ∼ = 350), slowly inactivates in the continued presence of Na + within the extracellular (extracytosolic) solution; outwardly rectifying

TRPP (polycystin) family
The 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. 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 (P Ca /P Na˜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 [82]. -

TRPV (vanilloid) family
Members 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. 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 [330,382,395]). Numerous splice vari-ants of TRPV1 have been described, some of which modulate the activity of TRPV1, or act in a dominant negative manner when coexpressed 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]. 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 [81,104,278,449]  Selective activators 6-tert-butyl-m-cresol (pEC 50 : an exhaustive listing can be found in [16]. In addition, TRPA1 is potently activated by intracellular zinc (EC 50 = 8 nM) [10,156].

TRPM (melastatin) family
Ca 2+ 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 [Ca 2+ ] i demonstrates a pronounced and time-dependent reduction following excision of inside-out membrane patches [418]. The V ½ 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 V ½ is shifted in the hyperpolarizing direction both by decreasing temperature and by exogenous agonists, such as (-)-menthol [423] whereas antagonists produce depolarizing shifts in V ½ [276]. The V ½ 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 Ca 2+ from the endoplasmic reticulum independent of activation of TRPM8 [254]. Intracellular pH modulates activation of TRPM8 by cold and icilin, but not (-)-menthol [9]. TRPML (mucolipin) family Data in the table are for TRPML proteins mutated (i.e TRPML1 Va , TRPML2 Va and TRPML3 Va ) 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]).

TRPP (polycystin) family
Data 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-  [88]. Ca 2+ , Ba 2+ and Sr 2+ permeate TRPP3, but reduce inward currents carried by Na + . Mg 2+ is largely impermeant and exerts a voltage dependent inhibition that increases with hyperpolarization. TRPV (vanilloid) family Activation of TRPV1 by depolarisation is strongly temperaturedependent via a channel opening rate that increases with increasing temperature. The V ½ 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 Ca 2+ under physiological conditions, but in the absence of extracellular Ca 2+ , conducts monovalent cations. Single channel conductances listed for TRPV5 and TRPV6 were determined in divalent cation-free extracellular solution. Ca 2+ -induced inactivation occurs at hyperpolarized potentials when Ca 2+ is present extracellularly. Single channel events cannot be resolved (proba-bly due to greatly reduced conductance) in the presence of extracellular divalent cations. Measurements of P Ca /P Na for TRPV5 and TRPV6 are dependent upon ionic conditions due to anomalous mole fraction behaviour. Blockade of TRPV5 and TRPV6 by extracellular Mg 2+ is voltage-dependent. Intracellular Mg 2+ 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 Ca 2+ -dependent inactivation and recovery from inactivation. TRPV5 and TRPV6 function as homoand hetero-tetramers.

Voltage-gated calcium channels
Voltage-gated ion channels → Voltage-gated calcium channels Overview: Calcium (Ca 2+ ) channels are voltage-gated ion channels present in the membrane of most excitable cells. The nomenclature for Ca 2+ channels was proposed by [101] and approved by the NC-IUPHAR Subcommittee on Ca 2+ channels [54]. Ca 2+ 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, Ca V 1.x) channels; (2) the high-voltage activated dihydropyridine-insensitive (Ca V 2.x) channels and (3) the low-voltage-activated (T-type, Ca V 3.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.

Voltage-gated proton channel
Voltage-gated ion channels → Voltage-gated proton channel Overview: The voltage-gated proton channel (provisionally denoted H v 1) 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 H v 1 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 H v 1 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]. H v 1 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].  [346,362]. Zn 2+ is not a conventional pore blocker, but is coordinated by two, or more, external protonation sites involving histamine residues [346]. Zn 2+ 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 H v 1 participates in charge compensation in granulocytes during the respiratory burst of NADPH oxidasedependent reactive oxygen species production that assists in the clearance of bacterial pathogens [347]. Additional physiological functions of H v 1 are reviewed by [49].

Voltage-gated sodium channels
Voltage-gated ion channels → Voltage-gated sodium channels Overview: Sodium channels are voltage-gated sodium-selective ion channels present in the membrane of most excitable cells. Sodium channels comprise of one pore-forming 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. The 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]).
Activation V 0.5 = -24 mV. Fast inactivation (τ = 0.8 ms for peak sodium current).  Comments: 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 dif-ferent subtypes. These are sensitivity to tetrodotoxin (Na V 1.5, Na V 1.8 and Na V 1.9 are much less sensitive to block) and rate of fast inactivation (Na V 1.8 and particularly Na V 1.9 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.