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.


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 º » mice [171] and also mature human sperm [215,343]. I CatSper is also undetectable in the spermatozoa of Catsper2 º » ,Catsper3 º » , Catsper4 º » , or CatSperAE º » mice, and CatSper 1 associates with CatSper 2, 3, 4, β, γ, and AE [59,218,299]. Moreover, targeted disruption of Catsper1, 2, 3, 4, or AE 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 Ca 2 entry into spermatozoa [47,59,299]. Thus, it is likely that the CatSper pore is formed by a heterotetramer of  in association with the auxiliary sub-units (β, γ, AE) that are also essential for function [59]. CatSper channels are required for the increase in intracellular Ca 2 concentration in sperm evoked by egg zona pellucida glycoproteins [404]. Mouse and human sperm swim against the fluid flow and Ca 2 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 Ca 2 signaling domains along the flagella, which orchestrate capacitation-associated tyrosine phosphorylation [60].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 [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 H v 1, a proton channel [216]. Mutations in CatSpers are associated with syndromic and nonsyndromic male infertility [128]. In human ejaculated spermatozoa, progesterone ( 50 nM) potentiates the CatSper current by a non-genomic mechanism and acts synergistically with intracel-lular alkalinisation [215,343]. Sperm cells from infertile patients with a deletion in CatSper2 gene lack I CatSper and the progesterone response [331]. In addition, certain prostaglandins (e.g. PGF 1α , PGE 1 ) 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)P 2 [387], intracellular ATP and extracellular amino acids [42]. TPCs are also involved in the NAADP-activated Ca 2 release from lysosomal Ca 2 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.

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 [138].
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 chan-nels 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.

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 volt-ages, thereby enhancing channel activity. HCN channels underlie pacemaker currents found in many excitable cells including cardiac cells and neurons [82,274]. In native cells, these currents have a variety of names, such as I h , I q andI f . The four known HCN channels have six transmembrane domains and form tetramers.
It is believed that the channels can form heteromers with each other, as has been shown for HCN1 and HCN4 [7]. A standardised nomenclature for HCN channels has been proposed by the NC-IUPHAR subcommittee on voltage-gated ion channels [138].  [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.

Potassium channels
Voltage-gated ion channels Potassium channels Overview: Potassium channels are fundamental regulators of excitability. They control the frequency and the shape of action potential waveform, the secretion of hormones and neurotransmitters and cell membrane potential. Their activity may be regulated by voltage, calcium and neurotransmitters (and the signalling pathways they stimulate). They consist of a primary pore-forming 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.

Inwardly rectifying potassium channels
Voltage-gated ion channels Potassium channels Inwardly rectifying potassium channels Overview: 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 (K ir 2.x), the G-protein-activated inward-rectifier K channels (K ir 3.x) and the ATP-sensitive K channels (K ir 6.x, which combine with sulphonylurea receptors (SUR)). The pore-forming a subunits form tetramers, and heteromeric channels may be formed within subfamilies (e.g. K ir 3.2 with K ir 3.3).  [90,190,192,277], Cs (Antagonist) (pK i 1.6) [voltage dependent -100mV] [90,190,277]

Two-P potassium channels
Voltage-gated ion channels Potassium channels Two-P potassium channels Overview: 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. K 2P 3.1 with K 2P 9.1). There is no current, clear, consensus on nomenclature of 4TM K channels, nor on the divi-sion into subfamilies [106]. The suggested division into subfamilies, below, is based on similarities in both structural and functional properties within subfamilies.
Functional Characteristics Background current Background current Background current. Knock-out of the kcnk3 gene leads to a prolonged QT interval in mice [77].

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 KCNQ subfamily, the EAG subfamily (which includes herg channels), the Ca 2 -activated Slo subfamily (actually with 6 or 7TM) and the Ca 2 -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.
Associated subunits ---MiRP2 is an associated subunit for K v 3.4

KChIP and KChAP
Functional Characteristics   [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)P 2 and IP 3 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]. Cova-lent 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 Ca 2 ions. A coiledcoil 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 q 11 -coupled receptors, or receptor tyrosine kinases (reviewed by [294,364,402]). A comprehensive listing of G-protein coupled receptors that activate TRPC channels is given in [2]. Hetero-oligomeric complexes of TRPC channels and their association with proteins to form signalling complexes are detailed in [8] and [173]. TRPC channels have frequently been proposed to act as store-operated channels (SOCs) (or compenents of mulimeric complexes that form SOCs), activated by depletion of intracellular calcium stores (reviewed by [8,56,285,295,315,416]), However, the weight of the evidence is that they are not directly gated by conventional store-operated mechanisms, as established for Stim-gated Orai channels. TRPC channels are not mechanically gated in physiologically relevant ranges of force. All members of the TRPC family are blocked by 2-APB and SKF96365 [124,125]. Activation of TRPC channels by lipids is discussed by [25].

TRPC1/C4/C5 subgroup
TRPC4/C5 may be distinguished from other TRP channels by their potentiation by micromolar concentrations of La 3 .

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 hTRPM3 1325 ) 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 Ca 2 [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 Ca 2 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 (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 [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 en-dosomes 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 coexpressed 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]

TRPA (ankyrin) family
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 (EC 50 = 8 nM) [11,140].

TRPM (melastatin) family
Ca 2 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 [Ca 2 ] i demonstrates a pronounced and time-dependent reduction following excision of inside-out membrane patches [366]. The V 1 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 V 1 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 V 1 2 [247]. The V 1 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 Ca 2 from the endoplasmic reticulum independent of activation of TRPM8 [229]. Intracellular pH modulates activation of TRPM8 by cold and icilin, but not (-)-menthol [10].

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 [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]).

TRPP (polycystin) family
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 coexpressed with TRPP1 [79]. 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 1 2 is shifted in the hyperpolarizing direction both by increasing temperature and by exogenous agonists [371]. The sensitivity of TRPV4 to heat, but not 4α-PDD is lost upon patch excision. TRPV4 is activated by anandamide and arachidonic acid following P450 epoxygenasedependent 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 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 (probably 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 timedependent 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 homo-and hetero-tetramers. Baraldi PG et al. (2010)

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 [92] and approved by the NC-IUPHAR Subcommittee on Ca 2 channels [50]. 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 highvoltage 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 coassemblies of α1, β and α2-AE subunits. The γ subunits have not been proven to associate with channels other than the α1s skeletal muscle Cav1.1 channel. The α2-AE1 and α2-AE2 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 [45,75,76,305,317]. 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 con-tains no discernable pore region [305,317]. 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 [304,401]. H v 1 expresses largely as a dimer mediated by intracellular C-terminal coiled-coil interactions [208] but individual promoters nonethe-less 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] .
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 (½pH = pH o -pH i ) across the membrane Channel blockers Zn 2 (pIC 50 5.7-6.3), Cd 2 (pIC 50 5)

Comments:
The voltage threshold (V thr ) for activation of Hv1 is not fixed but is set by the pH gradient across the membrane such that V thr is positive to the Nernst potential for H , which ensures that only outwardly directed flux of H occurs under physiological conditions [45,75,76] [305,317]. Zn 2 is not a conventional pore blocker, but is coordinated by two, or more, external protonation sites involving histamine residues [305]. Zn 2 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 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 [306]. Additional physiological functions of H v 1 are reviewed by [45].

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 [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 do-main, a single transmembrane segment and a shorter cytoplasmic domain.  -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.