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.14749. Ion channels are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, 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‐2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands ( Many ion channels  are gated by voltage but others  are relatively voltage‐insensitive and are gated by second messengers and other intracellular and/or extracellular mediators. As such, there is some blurring of the boundaries between “ion channels” and “ligand‐gated channels” which are compiled separately in the Guide. Resolution of ion channel structures, beginning with K channels [http://www.ncbi.nlm.nih.gov/pubmed/9525859?dopt=AbstractPlus] then Cl channels [http://www.ncbi.nlm.nih.gov/pubmed/11796999?dopt=AbstractPlus] and most recently Na channels [http://www.ncbi.nlm.nih.gov/pubmed/21743477?dopt=AbstractPlus] has greatly improved understanding of the structural basis behind ion channel function. Many ion channels  share several structural similarities. These channels are thought to have evolved from a common ancestor and have been classfied together as the “voltage‐gated‐like (VGL) ion channel chanome” (see [http://www.ncbi.nlm.nih.gov/pubmed/16382097?dopt=AbstractPlus]). Other ion channels, however, such as Cl channels, aquaporins and connexins, have completely different structural properties to the VGL channels, having evolved quite separately.Ion channels are pore‐forming proteins that allow the flow of ions across membranes, either plasma membranes, or the membranes of intracellular organelles [http://www.ncbi.nlm.nih.gov/pubmed/17139284?dopt=AbstractPlus]. However, the advent of novel, faster screening techniques for compounds acting on ion channels [http://www.ncbi.nlm.nih.gov/pubmed/18356919?dopt=AbstractPlus] suggests that these proteins represent promising targets for the development of additional, novel therapeutic agents for the near future.Currently, ion channels (including ligand‐gated ion channels) represent the second largest target for existing drugs after G protein‐coupled receptors , 5‐HT3 , ionotropic glutamate  and P2X receptors  and the inhibitory, anion‐selective, GABAA  and glycine receptors . The nicotinic acetylcholine, 5‐HT3, GABAA and glycine receptors  are pentameric structures and are frequently referred to as the Cysloop receptors due to the presence of a defining loop of residues formed by a disulphide bond in the extracellular domain of their constituent subunits . However, the prokaryotic ancestors of these receptors contain no such loop and the term pentameric ligand‐gated ion channel (pLGIC) is gaining acceptance in the literature [http://www.ncbi.nlm.nih.gov/pubmed/19646860?dopt=AbstractPlus]. The ionotropic glutamate and P2X receptors are tetrameric and trimeric structures, respectively. Multiple genes encode the subunits of LGICs and the majority of these receptors are heteromultimers. Such combinational diversity results, within eachclass of LGIC,in a widerangeof receptors withdiffering pharmacological and biophysical properties and varying patternsof expression within the nervous system and other tissues. The LGICs thus present attractive targets for new therapeutic agents with improved discrimination between receptor isoforms and a reduced propensity for off‐target effects. The development of novel, faster screening techniques for compounds acting on LGICs [http://www.ncbi.nlm.nih.gov/pubmed/18356919?dopt=AbstractPlus] will greatly aid in the development of such agents.By convention, the LGICs comprise the excitatory, cationselective, nicotinic acetylcholine [3 receptor (NC‐IUPHAR Subcommittee on 5‐Hydroxytryptamine (serotonin) receptorsnomenclature as agreed by the  [http://www.ncbi.nlm.nih.gov/pubmed/7938165?dopt=AbstractPlus]) is a ligand‐gated ion channel of the Cys‐loop family that includes the zinc‐activated channels, nicotinic acetylcholine, GABAA and strychnine‐sensitive glycine receptors. The receptor exists as a pentamer of 4TM subunits that form an intrinsic cation selective channel [http://www.ncbi.nlm.nih.gov/pubmed/18761359?dopt=AbstractPlus]. Five human 5‐HT3 receptor subunits have been cloned and homo‐oligomeric assemblies of 5‐HT3A and hetero‐oligomeric assemblies of 5‐HT3A and 5‐HT3B subunits have been characterised in detail. The 5‐HT3C , 5‐HT3D  and 5‐HT3E  subunits , like the 5‐HT3B subunit, do not form functional homomers, but are reported to assemble with the 5‐HT3A subunit to influence its functional expression rather than pharmacological profile . 5‐HT3A, ‐C, ‐D, and ‐E subunits also interact with the chaperone RIC‐3 which predominantly enhances the surface expression of homomeric 5‐HT3A receptor [http://www.ncbi.nlm.nih.gov/pubmed/20522555?dopt=AbstractPlus]. The co‐expression of 5‐HT3A and 5‐HT3C‐E subunits has been demonstrated in human colon [http://www.ncbi.nlm.nih.gov/pubmed/21192076?dopt=AbstractPlus]. A recombinant hetero‐oligomeric 5‐HT3AB receptor has been reported to contain two copies of the 5‐HT3A subunit and three copies of the 5‐HT3B subunit in theorderB‐B‐A‐B‐A[http://www.ncbi.nlm.nih.gov/pubmed/16116092?dopt=AbstractPlus], butthis is inconsistent with recent reports which show at least one A‐A interface . The 5‐HT3B subunit imparts distinctive biophysical properties upon hetero‐oligomeric 5‐HT3AB versus homo‐oligomeric 5‐HT3A recombinant receptors , influences the potency of channel blockers, but generally has only a modest effect upon the apparent affinity of agonists, or the affinity of antagonists  which may be explained by the orthosteric binding site residing at an interface formed between 5‐HT3A subunits . However, 5‐HT3A and 5‐HT3AB receptors differ in their allosteric regulation by some general anaesthetic agents, small alcohols and indoles . The potential diversity of 5‐HT3 receptors is increased by alternative splicing of the genes HTR3A and E . In addition, the use of tissue‐specific promoters driving expression from differenttranscriptional start sites has beenreported for theHTR3A, HTR3B,HTR3D and HTR3E genes, which could result in 5‐HT3 subunits harbouring different N‐termini . To date, inclusion of the 5‐HT3A subunit appears imperative for 5‐HT3 receptor function.The 5‐HT3A subunit, or the receptor native to human tissues. Significant changes introduced by co‐expression of the 5‐HT3B subunit are indicated in parenthesis. Although not a selective antagonist, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5458 displays multimodal and subunit‐dependent antagonism of 5‐HT3 receptors [http://www.ncbi.nlm.nih.gov/pubmed/19131665?dopt=AbstractPlus]. Similarly, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4323, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2298, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4051, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2366 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1862 are not selective for 5‐HT3 receptors (e.g.[http://www.ncbi.nlm.nih.gov/pubmed/21059362?dopt=AbstractPlus]). The anti‐malarial drugs http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4252and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2510 exerta modestly more potent block of 5‐HT3A versus 5‐HT3AB receptor‐mediated responses [http://www.ncbi.nlm.nih.gov/pubmed/18311193?dopt=AbstractPlus]. Knownbetterasa partial agonistof nicotinic acetylcholine α4β2 receptors, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5459 is also an agonist of the 5‐HT3A receptor [http://www.ncbi.nlm.nih.gov/pubmed/21775477?dopt=AbstractPlus]. Human , rat [http://www.ncbi.nlm.nih.gov/pubmed/7509203?dopt=AbstractPlus], mouse [http://www.ncbi.nlm.nih.gov/pubmed/1718042?dopt=AbstractPlus], guinea‐pig [http://www.ncbi.nlm.nih.gov/pubmed/9463477?dopt=AbstractPlus] ferret [http://www.ncbi.nlm.nih.gov/pubmed/10884508?dopt=AbstractPlus] and canine [http://www.ncbi.nlm.nih.gov/pubmed/16647053?dopt=AbstractPlus] orthologues of the 5‐HT3A receptor subunit have been cloned that exhibit intraspecies variations in receptor pharmacology. Notably, most ligands display significantly reduced affinities at the guinea‐pig 5‐HT3 receptor in comparison with other species. In addition to the agents listed in the table, native and recombinant 5‐HT3 receptors are subject to allosteric modulation by extracellular divalent cations, alcohols, several general anaesthetics and 5‐hydroxy‐ and halidesubstituted indoles .Quantitative data in the table refer to homooligomeric assemblies of the human 5‐HTet al. (2014) Nausea and the quest for the perfect anti‐emetic. Eur. J. Pharmacol.722: 108‐21 https://www.ncbi.nlm.nih.gov/pubmed/24157981?dopt=AbstractPlusAndrews PL et al. (2015) From Chemotherapy‐Induced Emesis to Neuroprotection: Therapeutic Opportunities for 5‐HT3 Receptor Antagonists. Mol. Neurobiol.52: 1670‐1679 https://www.ncbi.nlm.nih.gov/pubmed/25377794?dopt=AbstractPlusFakhfouri G et al. (2016) 5‐HT3 receptors: Target for new antidepressant drugs. Neurosci Biobehav Rev64: 311‐25 https://www.ncbi.nlm.nih.gov/pubmed/26976353?dopt=AbstractPlusGupta D et al. (1994) International Union of Pharmacology classification of receptors for 5‐hydroxytryptamine (Serotonin). Pharmacol. Rev.46: 157‐203 https://www.ncbi.nlm.nih.gov/pubmed/7938165?dopt=AbstractPlusHoyer D et al. (2015) A review of fluorescent ligands for studying 5‐HT3 receptors. Neuropharmacology98: 31‐40 https://www.ncbi.nlm.nih.gov/pubmed/25892507?dopt=AbstractPlusLochner M et al. (2014) Molecular mechanisms of 5‐HT(3) and NK(1) receptor antagonists in prevention of emesis. Eur. J. Pharmacol.722: 26‐37 https://www.ncbi.nlm.nih.gov/pubmed/24184669?dopt=AbstractPlusRojas C NC‐IUPHARnomenclatureas agreed by  [http://www.ncbi.nlm.nih.gov/pubmed/25287517?dopt=AbstractPlus]) are members of a Na+ channel superfamily that includes the epithelial Na+ channel (ENaC), the FMRF‐amide activated channel (FaNaC) of invertebrates, the degenerins (DEG) of Caenorhabitis elegans, channels in Drosophila melanogaster and ’orphan’ channels that include BLINaC [http://www.ncbi.nlm.nih.gov/pubmed/10457052?dopt=AbstractPlus] and INaC [http://www.ncbi.nlm.nih.gov/pubmed/10767424?dopt=AbstractPlus] that have also been named BASICs, for bile acidactivated ion channels [http://www.ncbi.nlm.nih.gov/pubmed/24365967?dopt=AbstractPlus]. ASIC subunits contain two TM domains and assemble as homo‐ or hetero‐trimers  to form proton‐gated, voltage‐insensitive, Na+ permeable, channels . Splice variants of ASIC1 [termed ASIC1a  [http://www.ncbi.nlm.nih.gov/pubmed/9062189?dopt=AbstractPlus], ASIC1b  [http://www.ncbi.nlm.nih.gov/pubmed/9707631?dopt=AbstractPlus] and ASIC1b2 (ASICβ2) [http://www.ncbi.nlm.nih.gov/pubmed/11588592?dopt=AbstractPlus]; note that ASIC1a is also permeable to Ca2+] and ASIC2  and ASIC2b  [http://www.ncbi.nlm.nih.gov/pubmed/9368048?dopt=AbstractPlus]] have been cloned. Unlike ASIC2a (listed in table), heterologous expression of ASIC2b alone does not support H+‐gated currents. A third member, ASIC3  [http://www.ncbi.nlm.nih.gov/pubmed/9261094?dopt=AbstractPlus], has been identified. A fourth mammalian member of the family (ASIC4/SPASIC) does not support a proton‐gated channel in heterologous expression systems and is reported to downregulate the expression of ASIC1a and ASIC3 . ASIC channels are primarily expressed in central and peripheral neurons including nociceptors where they participate in neuronal sensitivity to acidosis. They have also been detected in taste receptor cells (ASIC13), photoreceptors and retinal cells (ASIC1‐3), cochlear hair cells (ASIC1b), testis (hASIC3), pituitary gland (ASIC4), lung epithelial cells (ASIC1a and ‐3), urothelial cells, adipose cells (ASIC3), vascular smooth muscle cells (ASIC1‐3), immune cells  and bone (ASIC1‐3). A neurotransmitter‐like function of protons has been suggested, involving postsynaptically located ASICs of the CNS in functions such as learning and fear perception , responses to focal ischemia [http://www.ncbi.nlm.nih.gov/pubmed/17127388?dopt=AbstractPlus] and to axonal degeneration in autoimmune inflammation in a mouse model of multiple sclerosis [http://www.ncbi.nlm.nih.gov/pubmed/17994101?dopt=AbstractPlus], as well as seizures [http://www.ncbi.nlm.nih.gov/pubmed/18536711?dopt=AbstractPlus] and pain . Heterologously expressed heteromultimers form ion channels with differences in kinetics, ion selectivity, pH‐ sensitivity and sensitivity to blockers that resemble some of the native proton activated currents recorded from neurones .Acid‐sensing ion channels  inhibits ASIC1a by increasing the affinity toH+and promoting channel desensitization . PcTx1 has little effect on ASIC2a, ASIC3 or ASIC1a expressed as a heteromultimer with either ASIC2a, or ASIC3 but does inhibit ASIC1a expressed as a heteromultimer with ASIC2b [http://www.ncbi.nlm.nih.gov/pubmed/21715637?dopt=AbstractPlus]. PcTx1 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=10305 potentiate ASIC1b currents . ASIC1containing homo‐ and heteromers are inhibited by Mambalgins, toxins contained in the black mamba venom, which induce in ASIC1a an acidic shift of the pH dependence of activation [http://www.ncbi.nlm.nih.gov/pubmed/23034652?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=10306 is highly selective for ASIC1a with very little activity at ASIC1b. It inhibits channel activation and is very slowly reversible [http://www.ncbi.nlm.nih.gov/pubmed/28320941?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4135 most potently blocks homomeric ASIC3 channels, but also ASIC2b+ASIC3, ASIC1b+ASIC3, and ASIC1a+ASIC3 heteromeric channels with IC50 values of 117 nM, 900 nM and 2 μM, respectively. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4135 has no effect on ASIC1a or ASIC2a+ASIC3, however, it does potentiate ASIC1b and ASIC2a homomers in the low micromolar range(1‐10μM) . http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4135however also inhibits voltage‐gated Na+ channels . IC50 value for http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4116 was determined using high throughput electrophysiology on human ASIC3 expressed in HEK293 cells [http://www.ncbi.nlm.nih.gov/pubmed/22778804?dopt=AbstractPlus]. The pEC50 values for proton activation of ASIC channels are influenced by numerous factors including extracellular di‐ and poly‐valent ions, Zn2+, protein kinase C and serine proteases . Rapid acidification is required for activation of ASIC1 and ASIC3 due to fast inactivation/desensitization. pEC50 values for H+‐activation of either transient, or sustained, currents mediated by ASIC3 vary in the literature and may reflect species and/or methodological differences . The transient ASIC current component is Na+‐selective (PNa/PK of about 10)  whereas the sustained current component that is observed with ASIC3 and some ASIC heteromers is non‐selective between Na+ and K+ [http://www.ncbi.nlm.nih.gov/pubmed/9744806?dopt=AbstractPlus]. The reducing agents dithiothreitol (DTT) and glutathione (GSH) increase ASIC1a currents expressed in CHO cells and ASIC‐like currents in sensory ganglia and central neurons  whereas oxidation, through the formation of intersubunit disulphide bonds, reduces currents mediated by ASIC1a [http://www.ncbi.nlm.nih.gov/pubmed/19218436?dopt=AbstractPlus]. ASIC1a is also irreversibly modulated by extracellular serine proteases, such as trypsin, through proteolytic cleavage [http://www.ncbi.nlm.nih.gov/pubmed/16282326?dopt=AbstractPlus]. Non‐steroidal anti‐inflammatory drugs (NSAIDs) are direct inhibitors of ASIC currents (reviewed in [http://www.ncbi.nlm.nih.gov/pubmed/25613302?dopt=AbstractPlus]). Extracellular Zn2+ potentiates proton activation of homomeric and heteromeric channels incorporating ASIC2a, but not homomeric ASIC1a or ASIC3 channels [http://www.ncbi.nlm.nih.gov/pubmed/11457851?dopt=AbstractPlus]. However, removal of contaminating Zn2+ by chelation reveals a high affinity block of homomeric ASIC1a and heteromeric ASIC1a+ASIC2 channels by Zn2+ indicating complex biphasic actions of the divalent [http://www.ncbi.nlm.nih.gov/pubmed/15470133?dopt=AbstractPlus]. Nitric oxide potentiates submaximal currents activated by H+ mediated by ASIC1a, ASIC1b, ASIC2a and ASIC3 [http://www.ncbi.nlm.nih.gov/pubmed/18045919?dopt=AbstractPlus]. Ammonium ions activate ASIC channels (most likely ASIC1a) in midbrain dopaminergic neurones: that may be relevant to neuronal disorders associated with hyperammonemia [http://www.ncbi.nlm.nih.gov/pubmed/16847263?dopt=AbstractPlus]. The positive modulation of homomeric, heteromeric and native ASIC channels by the peptide http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4195 and related substances, such as neuropeptides FF and SF, is reviewed in detail in [http://www.ncbi.nlm.nih.gov/pubmed/25592215?dopt=AbstractPlus]. Inflammatory conditions and particular pro‐inflammatory mediators such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2391 induce overexpression of ASIC‐encoding genes and enhance ASIC currents . The sustained current component mediated by ASIC3 is potentiated by hypertonic solutions in a manner that is synergistic with the effect of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2391 [http://www.ncbi.nlm.nih.gov/pubmed/18923424?dopt=AbstractPlus]. ASIC3 is partially activated by the lipids lysophosphatidylcholine (LPC) and arachidonic acid [http://www.ncbi.nlm.nih.gov/pubmed/26772186?dopt=AbstractPlus]. Mit‐Toxin, which is contained in the venom of the Texas coral snake, activates several ASIC subtypes [http://www.ncbi.nlm.nih.gov/pubmed/22094702?dopt=AbstractPlus]. Selective activation of ASIC3 by GMQ at a site separate from the proton binding site is potentiated by mild acidosis and reduced extracellular Ca2+ [http://www.ncbi.nlm.nih.gov/pubmed/20920791?dopt=AbstractPlus].et al. (2015) Pharmacology of acid‐sensing ion channels ‐ Physiological and therapeutical perspectives. Neuropharmacology94: 19‐35 https://www.ncbi.nlm.nih.gov/pubmed/25613302?dopt=AbstractPlusBaron A et al. (2016) The function and regulation of acid‐sensing ion channels (ASICs) and the epithelial Na(+) channel (ENaC): IUPHAR Review 19. Br. J. Pharmacol.173: 2671‐701 https://www.ncbi.nlm.nih.gov/pubmed/27278329?dopt=AbstractPlusBoscardin E et al. (2017) Acid‐sensing ion channel (ASIC) structure and function: Insights from spider, snake and sea anemone venoms. Neuropharmacology127: 173‐184 https://www.ncbi.nlm.nih.gov/pubmed/28457973?dopt=AbstractPlusCristofori‐Armstrong B et al. (2015) Biophysical properties of acid‐sensing ion channels (ASICs). Neuropharmacology94: 9‐18 https://www.ncbi.nlm.nih.gov/pubmed/25585135?dopt=AbstractPlusGründer S FEBS J.284: 525‐545 https://www.ncbi.nlm.nih.gov/pubmed/27580245?dopt=AbstractPlusHanukoglu I. (2017) ASIC and ENaC type sodium channels: conformational states and the structures of the ion selectivity filters. et al. (2015) International Union of Basic and Clinical Pharmacology. XCI. structure, function, and pharmacology of acid‐sensing ion channels and the epithelial Na+ channel. Pharmacol. Rev.67: 1‐35 https://www.ncbi.nlm.nih.gov/pubmed/25287517?dopt=AbstractPlusKellenberger S Adv. Pharmacol.79: 35‐66 https://www.ncbi.nlm.nih.gov/pubmed/28528673?dopt=AbstractPlusRash LD. (2017) Acid‐Sensing Ion Channel Pharmacology, Past, Present, and Future …. http://www.ncbi.nlm.nih.gov/pubmed/7810611?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/7806569?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/26772908?dopt=AbstractPlus]. In these epithelia, ENaC allows flow of Na+ ions from the extracellular fluid in the lumen into the epithelial cell. Na+ ions are then pumped out of the cytoplasm into the interstitial fluid by the Na+/K+ ATPase located on the basolateral membrane [http://www.ncbi.nlm.nih.gov/pubmed/16139686?dopt=AbstractPlus]. As Na+ is one of the major electrolytes in the extracellular fluid (ECF), osmolarity change initiated by the Na+ flow is accompanied by a flow of water accompanying Na+ ions [http://www.ncbi.nlm.nih.gov/pubmed/18509340?dopt=AbstractPlus]. Thus, ENaC has a central role in the regulation of ECF volume and blood pressure, especially via its function in the kidney . The expression of ENaC subunits, hence its activity, is regulated by the renin‐angotensin‐aldosterone system, and other factors that are involved in electrolyte homeostasis . In the respiratory tract and female reproductive tract large segments of the tracts are covered by multi‐ciliated cells. In these cells ENaC has been shown to be located along the entire length of the cilia [http://www.ncbi.nlm.nih.gov/pubmed/22207244?dopt=AbstractPlus]. Cilial location greatly increases ENaC density per cell surface and allows ENaC to serve as a sensitive regulator of osmolarity of the periciliary fluid throughout the whole depth of the fluid bathing the cilia [http://www.ncbi.nlm.nih.gov/pubmed/22207244?dopt=AbstractPlus]. In contrast to ENaC, CFTR that is defective in cystic fibrosis is not located on non‐cilial cell‐surface [http://www.ncbi.nlm.nih.gov/pubmed/22207244?dopt=AbstractPlus]. Thus, ENaC function is also essential for the clearance of respiratory airways, transport of germ cells, fertilization, implantation and cell migration . ENaC has beenrecently localized in the germinal epithelium of the testis, Sertoli cells, spermatozoa, along the epididymis ducts, and smooth muscle cells . Evidence has been provided that rare mutations in ENaC are associated with female infertility [http://www.ncbi.nlm.nih.gov/pubmed/29885352?dopt=AbstractPlus].The epithelial sodium channels (ENaC) are located on the apical membrane of epithelial cells in the distal kidney tubules, lung, respiratory tract, male and female reproductive tracts, sweat and salivary glands, placenta, colon and some other organs . GABAA receptors exist as pentamers of 4TM subunits that form an intrinsic anion selective channel. Sequences of six α, three β, three γ, one δ, three ρ, one∈, one π and one ϑ GABAA receptor subunits have been reported in mammals . The π‐subunit is restricted to reproductive tissue. Alternatively spliced versions of many subunits exist  α5‐, β2‐, β3‐ and γ2), along with RNA editing of the α3 subunit [http://www.ncbi.nlm.nih.gov/pubmed/19909284?dopt=AbstractPlus]. The three ρ‐subunits, (ρ1‐3) function as either homo‐or hetero‐oligomeric assemblies . Receptors formed from ρ‐subunits, because of their distinctive pharmacology that includes insensitivity tobicuculline, benzodiazepines and barbiturates, have sometimes been termed GABAC receptors [http://www.ncbi.nlm.nih.gov/pubmed/11239575?dopt=AbstractPlus], A receptors by NC‐IUPHAR on the basis of structural and functional criteriabut they are classified as GABA .The GABAA receptor subtypes contain α‐, β‐ and γ‐subunits with the likely stoichiometry 2α.2β.1γ. It is thought that the majority of GABAA receptors harbour a single type of α‐ and β ‐subunit variant. The α1β2γ2 hetero‐oligomer constitutes the largest population of GABAA receptors in the CNS, followed by the α2β3γ2 and α3β3γ2 isoforms. Receptors that incorporate the α4‐ α5‐or α6‐subunit, or the β1‐, γ1‐, γ3‐, δ‐, ∈‐ and ϑ‐subunits, are less numerous, but they may nonetheless serve important functions. For example, extrasynaptically located receptors that contain α6‐ and δ‐subunits in cerebellar granule cells, or an α4‐ and δ‐subunit in dentate gyrus granule cells and thalamic neurones, mediate a tonic current that is important for neuronal excitability in response to ambient concentrations of GABA . GABA binding occurs at the β+/α‐ subunit interface and the homologous γ+/α‐ subunits interface creates the benzodiazepinesite. A second site for benzodiazepine binding hasrecently been postulated to occur at the α+/β‐ interface . The particular α‐and γ‐subunit isoforms exhibit marked effects on recognition and/or efficacy at the benzodiazepine site. Thus, receptors incorporating either α4‐ or α6‐subunits are not recognised by ‘classical’ benzodiazepines, such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4193 (but see [http://www.ncbi.nlm.nih.gov/pubmed/20638393?dopt=AbstractPlus]). The trafficking, cell surface expression, internalisation and function of GABAA receptors and their subunits are discussed in detail in several recent reviews  but one point worthy of note is that receptors incorporating the γ2 subunit (except when associated with α5) cluster at the postsynaptic membrane , whereas as those incorporating the d subunit appear to be exclusively extrasynaptic.Many GABANC‐IUPHAR  class the GABAA receptors according to their subunit structure, pharmacology and receptor function. Currently, eleven native GABAA receptors are classed as conclusively identified  with further receptor isoforms occurring with high probability, or only tentatively . It is beyond the scope of this Guide to discuss the pharmacology of individual GABAA receptor isoforms in detail; such information can be gleaned in the reviews  and . Agents that discriminate between α‐subunit isoforms are noted in the table and additional agents that demonstrate selectivity between receptor isoforms, for example via β‐subunit selectivity, are indicated in the text below. The distinctive agonist and antagonist pharmacology of ρ receptors is summarised in the table and additional aspects are reviewed in .A receptor in lipid nanodiscs is bound to the channel‐blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA (γ‐aminobutyric acid), and the classical benzodiazepines alprazolam and diazepam [http://www.ncbi.nlm.nih.gov/pubmed/30602790?dopt=AbstractPlus].Several high‐resolution cryo‐electron microscopy structures have been described in which the full‐length human α1β3γ2L GABAA receptor isoforms . For example, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4322 is a partial agonist at receptors with the subunit composition α4β3γ2, but elicits currents in excess of those evoked by GABA at the α4β3δ receptor where GABA itself is a low efficacy agonist . The antagonists http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2312 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4197 differ in their ability to suppress spontaneous openings of the GABAA receptor, the former being more effective [http://www.ncbi.nlm.nih.gov/pubmed/10455284?dopt=AbstractPlus]. The presence of the γ subunit within the heterotrimeric complex reduces the potency and efficacy of agonists [http://www.ncbi.nlm.nih.gov/pubmed/16272218?dopt=AbstractPlus]. The GABAA receptor contains distinct allosteric sites that bind barbiturates and endogenous  and synthetic  neuroactive steroids in a diastereo‐ or enantio‐selective manner . Picrotoxinin and TBPS act at an allosteric site within the chloride channel pore to negatively regulate channel activity; negative allosteric regulation by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5462 derivatives also involves the http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2291 site, whereas positive allosteric regulation by such compounds is proposed to occur at a distinct locus. Many intravenous  and inhalational  anaesthetics and alcohols also exert a regulatory influence upon GABAA receptor activity . Specific amino acid residues within GABAA receptor α‐ and β‐subunits that influence allosteric regulation by anaesthetic and non‐anaesthetic compounds havebeen identified . Photoaffinity labelling of distinct amino acid residues within purified GABAA receptors by the etomidate derivative, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5404, has also been demonstrated [http://www.ncbi.nlm.nih.gov/pubmed/17093081?dopt=AbstractPlus] and this binding subject to positive allosteric regulation by anaesthetic steroids [http://www.ncbi.nlm.nih.gov/pubmed/19282280?dopt=AbstractPlus]. An array of natural products including flavonoid and terpenoid compounds exert varied actions at GABAA receptors (reviewed in detail in [http://www.ncbi.nlm.nih.gov/pubmed/15974965?dopt=AbstractPlus]).The potency and efficacy of many GABA agonists vary between GABAA receptor activity that exhibit subunit dependent activity include: http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5465 ]; fragrent dioxane derivatives ]; http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5466, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5463, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5467, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2593, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5468, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5469, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5470 ]; http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5467 ]; http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2421 [selective blockade of receptors containing an α6‐subunit [http://www.ncbi.nlm.nih.gov/pubmed/12021393?dopt=AbstractPlus]]; http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4839 ]; http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2434 ]; http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2299 , but see also [http://www.ncbi.nlm.nih.gov/pubmed/17591542?dopt=AbstractPlus]]; http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4183 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4184 [selectively potentiate responses mediated by δ‐subunitcontaining receptors [http://www.ncbi.nlm.nih.gov/pubmed/18762200?dopt=AbstractPlus]]. It should be noted that the apparent selectivity of some positive allosteric modulators  may be a consequence of the unusually low efficacy of GABA at this receptor isoform .In addition to the agents listed in the table, modulators of GABACNS Neurosci Ther14: 25‐35 https://www.ncbi.nlm.nih.gov/pubmed/18482097?dopt=AbstractPlusAtack JR. (2008) GABA(A) receptor subtype‐selective efficacy: TPA023, an alpha2/alpha3 selective non‐sedating anxiolytic and alpha5IA, an alpha5 selective cognition enhancer. et al. (2015) The GABAA Receptor as a Therapeutic Target for Neurodevelopmental Disorders. Neuron86: 1119‐30 https://www.ncbi.nlm.nih.gov/pubmed/26050032?dopt=AbstractPlusBraat S et al. (2016) Dynamic Regulation of the GABAA Receptor Function by Redox Mechanisms. Mol. Pharmacol.90: 326‐33 https://www.ncbi.nlm.nih.gov/pubmed/27439531?dopt=AbstractPlusCalvo DJ et al. (2019) GABA_A receptor signalling mechanisms revealed by structural pharmacology. Nature565: 454‐459 https://www.ncbi.nlm.nih.gov/pubmed/30602790?dopt=AbstractPlusMasiulis S et al. (2016) Role of GABA_A R trafficking in the plasticity of inhibitory synapses. J. Neurochem.139: 997‐1018 https://www.ncbi.nlm.nih.gov/pubmed/27424566?dopt=AbstractPlusMele M NC‐IUPHAR Subcommittee on Glycine Receptorsnomenclature as agreed by the ) is a member of the Cys‐loop superfamily of transmittergated ion channels that includes the zinc activated channels, GABAA, nicotinic acetylcholine and 5‐HT3 receptors [http://www.ncbi.nlm.nih.gov/pubmed/18721822?dopt=AbstractPlus]. The receptor is expressed either as a homo‐pentamer of α subunits, or a complex now thought to harbour 2α and 3β subunits , that contain an intrinsic anion channel. Four differentially expressed isoforms of the α‐subunit (α1‐α4) and one variant of the β‐subunit  have been identified by genomic and cDNA cloning. Further diversity originates from alternative splicing of the primary gene transcripts for α1 (α1INS and α1del), α2 (α2A and α2B), α3 (α3S and α3L) and β (βΔ7) subunits and by mRNA editing of the α2 and α3 subunit . Both α2 splicing and α3 mRNA editing can produce subunits  with enhanced agonist sensitivity. Predominantly, the mature form of the receptor contains α1 (or α3) and β subunits while the immature form is mostly composed of only α2 subunits. RNA transcripts encoding the α4‐subunit have not been detected in adult humans. The N‐terminal domain of the α‐subunit contains both the agonist and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=347 binding sites that consist of several discontinuous regions of amino acids. Inclusion of the β‐subunit in the pentameric glycine receptor contributes to agonist binding, reduces single channel conductance and alters pharmacology. The β‐subunit also anchors the receptor, via an amphipathic sequence within the large intracellular loop region, to gephyrin. The latter is a cytoskeletal attachment protein that binds to a number of subsynaptic proteins involved in cytoskeletal structure and thus clusters and anchors hetero‐oligomeric receptors to the synapse . G‐protein βγ subunits enhance the open state probability of native and recombinant glycine receptors by association with domains within the large intracellular loop . Intracellular chloride concentration modulates the kinetics of native and recombinant glycine receptors [http://www.ncbi.nlm.nih.gov/pubmed/18987182?dopt=AbstractPlus]. Intracellular Ca2+ appears to increase native and recombinant glycine receptor affinity, prolonging channel open events, by a mechanism that does not involve phosphorylation [http://www.ncbi.nlm.nih.gov/pubmed/11144365?dopt=AbstractPlus].The inhibitory glycine receptor . http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4290, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=260 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2367, for example, although not selective antagonists of glycine receptors, are included for this purpose. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=347 is a potent and selective competitive glycine receptor antagonist with affinities in the range 5–15 nM. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2378 demonstrates comparable potency, but additionally blocks GABAA receptors. There are conflicting reports concerning the ability of cannabinoids to inhibit [http://www.ncbi.nlm.nih.gov/pubmed/16107637?dopt=AbstractPlus], or potentiate and at high concentrations activate  glycine receptors. Nonetheless, cannabinoid analogues may hold promise in distinguishing between glycine receptor subtypes [http://www.ncbi.nlm.nih.gov/pubmed/18755158?dopt=AbstractPlus]. In addition, potentiation of glycine receptor activity by cannabinoids has been claimed to contribute to cannabis‐induced analgesia relying on Ser296/307 (α1/α3) in M3 [http://www.ncbi.nlm.nih.gov/pubmed/21460829?dopt=AbstractPlus]. Several analogues of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4259 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5477 act as agonists and antagonists of both glycine and GABAA receptors. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4051 acts as an allosteric inhibitor that appears to bind within the pore, and shows strong selectivity towards homomeric receptors. While its components, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2291 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4286, have equal potencies at α1 receptors, their potencies at α2 and α3 receptors differ modestly and may allow some distinction between different receptor types [http://www.ncbi.nlm.nih.gov/pubmed/17714449?dopt=AbstractPlus]. Binding of picrotoxin within the pore has been demonstrated in the crystal structure of the related C. elegans GluCl Cys‐loop receptor [http://www.ncbi.nlm.nih.gov/pubmed/21572436?dopt=AbstractPlus]. In addition to the compounds listed in the table, numerous agents act as allosteric regulators of glycine receptors . Zn2+ acts through distinct binding sites of high‐ and low‐affinity to allosterically enhance channel function at low (<10 μM) concentrations and inhibits responses at higher concentrations in a subunit selective manner [http://www.ncbi.nlm.nih.gov/pubmed/15905212?dopt=AbstractPlus]. The effect of Zn2+ is somewhat mimicked by Ni2+. Endogenous Zn2+ is essential for normal glycinergic neurotransmission mediated by α1 subunit‐containing receptors [http://www.ncbi.nlm.nih.gov/pubmed/17114051?dopt=AbstractPlus]. Elevation of intracellular Ca2+ produces fast potentiation of glycine receptor‐mediated responses. Dideoxyforskolin (4 μM) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1016 (0.2–5 μM) both potentiate responses to low glycine concentrations (15 μM), but act as inhibitors at higher glycine concentrations (100 μM). Additional modulatory agents that enhance glycine receptor function include inhalational, and several intravenous general anaesthetics  and certain neurosteroids. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2299 and higher order n‐alcohols also enhance glycine receptor function although whether this occurs by a direct allosteric action at the receptor [http://www.ncbi.nlm.nih.gov/pubmed/10908659?dopt=AbstractPlus], or through βγ subunits [http://www.ncbi.nlm.nih.gov/pubmed/20647311?dopt=AbstractPlus] is debated. Recent crystal structures of the bacterial homologue, GLIC, have identified transmembrane binding pockets for both anaesthetics [http://www.ncbi.nlm.nih.gov/pubmed/21248852?dopt=AbstractPlus] and alcohols [http://www.ncbi.nlm.nih.gov/pubmed/21730162?dopt=AbstractPlus]. Solvents inhaled as drugs of abuse  may act at sites that overlap with those recognising alcohols and volatile anaesthetics to produce potentiation of glycine receptor function. The function of glycine receptors formed as homomeric complexes of α1 or α2 subunits, or hetero‐oligomers of α1/β or α2/β subunits, is differentially affected by the 5‐HT3 receptor antagonist tropisetron (ICS 205‐930) which may evoke potentiation (which may occur within the femtomolar range at the homomeric glycine α1 receptor), or inhibition, depending upon the subunit composition of the receptor and the concentrations of the modulator and glycine employed. Potentiation and inhibition by tropeines involves different binding modes [http://www.ncbi.nlm.nih.gov/pubmed/19383091?dopt=AbstractPlus]. Additional tropeines, including http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=320, modulate glycine receptor activity.Data in the table refer to homo‐oligomeric assemblies of the α‐subunit, significant changes introduced by coexpression of the β1 subunit are indicated in parenthesis. Not all glycine receptor ligands are listed within the table, but some that may be useful in distinguishing between glycine receptor isoforms are indicated  Structure and Pharmacologic Modulation of Inhibitory Glycine Receptors. Mol. Pharmacol. 90: 318‐25 https://www.ncbi.nlm.nih.gov/pubmed/27401877?dopt=AbstractPlusBurgos CF et al. (2012) Inhibitory glycine receptors: an update. J. Biol. Chem. 287: 40216‐23 https://www.ncbi.nlm.nih.gov/pubmed/23038260?dopt=AbstractPlusDutertre S Physiol. Rev.84: 1051‐95 https://www.ncbi.nlm.nih.gov/pubmed/15383648?dopt=AbstractPlusLynch JW. (2004) Molecular structure and function of the glycine receptor chloride channel. et al. (2010) Molecular targets and mechanisms for ethanol action in glycine receptors. Pharmacol. Ther. 127: 53‐65 https://www.ncbi.nlm.nih.gov/pubmed/20399807?dopt=AbstractPlusPerkins DI et al. (2011) Allosteric modulation of glycine receptors. Br. J. Pharmacol. 164: 224‐36 https://www.ncbi.nlm.nih.gov/pubmed/21557733?dopt=AbstractPlusYevenes GE http://www.ncbi.nlm.nih.gov/pubmed/10049997?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/18765242?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/20716669?dopt=AbstractPlus]. Receptor heterogeneity within each class arises from the homo‐oligomeric, or hetero‐oligomeric, assembly of distinct subunits into cation‐selective tetramers. Each subunit of the tetrameric complex comprises an extracellular amino terminal domain (ATD), an extracellular ligand binding domain (LBD), three transmembrane domains composed of three membrane spans , a channel lining re‐entrant ‘p‐loop’ (M2) located between M1 and M3 and an intracellular carboxy‐ terminal domain (CTD) . The X‐ray structure of a homomeric ionotropic glutamate receptor (GluA2 – see below) has recently been solved at 3.6Å resolution [http://www.ncbi.nlm.nih.gov/pubmed/19946266?dopt=AbstractPlus] and although providing the most complete structural information current available may not representative of the subunit arrangement of, for example, the heteromeric NMDA receptors [http://www.ncbi.nlm.nih.gov/pubmed/21677647?dopt=AbstractPlus]. It is beyond the scope of this supplement to discuss the pharmacology of individual ionotropic glutamate receptor isoforms in detail; such information can be gleaned from . Agents that discriminate between subunit isoforms are, where appropriate, noted in the tables and additional compounds that distinguish between receptor isoforms are indicated in the text below.The ionotropic glutamate receptors comprise members of the NMDA (N‐methyl‐D‐aspartate), AMPA (α‐amino3‐hydroxy‐5‐methyl‐4‐isoxazoleproprionic acid) and kainate receptor classes, named originally according to their preferred, synthetic, agonist [NC‐IUPHARThe classification of glutamate receptor subunits has been re‐addressed by  [http://www.ncbi.nlm.nih.gov/pubmed/18655795?dopt=AbstractPlus]. The scheme developed recommends a nomenclature for ionotropic glutamate receptor subunits that is adopted here.http://www.ncbi.nlm.nih.gov/pubmed/18026130?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/21521608?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/18514334?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/20134027?dopt=AbstractPlus]). Functional kainate receptors can be expressed as homomers of GluK1, GluK2 or GluK3 subunits. GluK1‐3 subunits are also capable of assembling into heterotetramers . Two additional kainate receptor subunits, GluK4 and GluK5, when expressed individually, form high affinity binding sites for http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4231, but lack function, but can form heteromers when expressed with GluK1‐3 subunits . Kainate receptors may also exhibit ‘metabotropic’ functions . As found for AMPA receptors, kainate receptors are modulated by auxiliary subunits . An important function difference between AMPA and kainate receptors is that the latter require extracellular Na+ and Cl‐ for their activation . RNA encoding the GluA2 subunit undergoes extensive RNA editing in which the codon encoding a p‐loop glutamine residue (Q) is converted to one encoding arginine (R). This Q/R site strongly influences the biophysical properties of the receptor. Recombinant AMPA receptors lacking RNA edited GluA2 subunits are: (1) permeable to Ca2+; (2) blocked by intracellular polyamines at depolarized potentials causing inward rectification (the latter being reduced by TARPs); (3) blocked by extracellular argiotoxin and Joro spider toxins and (4) demonstrate higher channel conductances than receptors containing the edited form of GluA2 . GluK1 and GluK2, but not other kainate receptor subunits, are similarly edited and broadly similar functional characteristics apply to kainate receptors lacking either an RNA edited GluK1, or GluK2, subunit . Native AMPA and kainate receptors displaying differential channel conductances, Ca2+ permeabilites and sensitivity to block by intracellular polyamines have been identified . GluA1‐4 can exist as two variants generated by alternative splicing (termed ‘flip’ and ‘flop’) that differ in their desensitization kinetics and their desensitization in the presence of cyclothiazide which stabilises the nondesensitized state. TARPs also stabilise the non‐desensitized conformation of AMPA receptors and facilitate the action of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4167 [http://www.ncbi.nlm.nih.gov/pubmed/18514334?dopt=AbstractPlus]. Splice variants of GluK1‐3 also exist which affects their trafficking .AMPA receptors assemble as homomers, or heteromers, that may be drawn from GluA1, GluA2, GluA3 and GluA4 subunits. Transmembrane AMPA receptor regulatory proteins (TARPs) of class I  act, with variable stoichiometry, as auxiliary subunits to AMPA receptors and influence their trafficking, single channel conductance gating and pharmacology  with relatively low potency, (EC50 100 μM). Inclusion of TARPs within the receptor complex increases the potency and maximal effect of kainate . AMPA is weak partial agonist at GluK1 and at heteromeric assemblies of GluK1/GluK2, GluK1/GluK5 and GluK2/GluK5 [http://www.ncbi.nlm.nih.gov/pubmed/18793656?dopt=AbstractPlus]. Quinoxalinediones such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5475 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4264 show limited selectivity between AMPA and kainate receptors. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4245 also has kainate (GluK1) receptor activity as has http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4209 (GluK3 and GluK2/GluK3) [http://www.ncbi.nlm.nih.gov/pubmed/18793656?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4141 is a potent competitive antagonist of AMPA receptors, has a weaker antagonist action at kainate receptors comprising GluK1 subunits, butis devoid of activity at kainate receptors formed from GluK2 or GluK2/GluK5 subunits. The pharmacological activity of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4141 resides with the (S)‐enantiomer. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4123 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4334 may block GluK3, in addition to GluK1 . ‐4‐methylglutamate (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4317) is equipotent in activating (and desensitising) GluK1 and GluK2 receptor isoforms and, via the induction of desensitisation at low concentrations, has beenused as a functional antagonist of kainate receptors. Both ‐4‐methylglutamate and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4246 have agonist activity at NMDA receptors. ‐4‐methylglutamate is also an inhibitor of the glutamate transporters EAAT1 and EAAT2.All AMPA receptors are additionally activated by http://www.ncbi.nlm.nih.gov/pubmed/16474411?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15701057?dopt=AbstractPlus]. The minimal requirement for efficient functional expression of NMDA receptors in vitro is a di‐heteromeric assembly of GluN1 and at least one GluN2 subunit variant, as a dimer of heterodimers arrangement in the extracellular domain . However, more complex tri‐heteromeric assemblies, incorporating multiple subtypes of GluN2 subunit, or GluN3 subunits, can be generatedin vitro and occurin vivo. The NMDA receptor channel commonly has a high relative permeability to Ca2+ and is blocked, in a voltage‐dependent manner, by Mg2+ such that at resting potentials the response is substantially inhibited.NMDA receptors assemble as obligate heteromers that may be drawn from GluN1, GluN2A, GluN2B, GluN2C, GluN2D, GluN3A and GluN3B subunits. Alternative splicing can generate eight isoforms of GluN1 with differing pharmacological properties. Various splice variants of GluN2B, 2C, 2D and GluN3A have also been reported. Activation of NMDA receptors containing GluN1 and GluN2 subunits requires the binding of two agonists, glutamate to the S1 and S2 regions of the GluN2 subunit and glycine to S1 and S2 regions of the GluN1 subunit . In addition to the glutamate and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=727 binding sites documented in the table, physiologically important inhibitory modulatory sites exist for Mg2+, Zn2+, and protons . Voltage‐independent inhibition by Zn2+ binding with high affinity within the ATD is highly subunit selective . The receptor is also allosterically modulated, in both positive and negative directions, by endogenous neuroactive steroids in a subunit dependent manner . Tonic proton blockade of NMDA receptor function is alleviated by polyamines and the inclusion of exon 5 within GluN1 subunit splice variants, whereas the non‐competitive antagonists http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5472 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4163 increase the fraction of receptors blocked by protons at ambient concentration. Inclusion of exon 5 also abolishes potentiation by polyamines and inhibition by Zn2+ that occurs through binding in the ATD [http://www.ncbi.nlm.nih.gov/pubmed/9698310?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5472, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4163, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=86, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5473 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4300 discriminate between recombinant NMDA receptors assembled from GluN1 and either GluN2A, or GluN2B, subunits by acting as selective, non‐competitive, antagonists of heterooligomers incorporating GluN2B through a binding site at the ATD GluN1/GluN2B subunit interface [http://www.ncbi.nlm.nih.gov/pubmed/21677647?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4244 is a competitive antagonist that also displays selectivity for GluN2B over GluN2A subunit‐containing receptors. Similarly, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5474 is a photoaffinity label that interacts selectively with receptors incorporating GluN2B versus GluN2A, GluN2D and, to a lesser extent, GluN2C subunits. TCN 201 and TCN 213 have recently been shown to block GluN2A NMDA receptors selectively by a mechanism that involves allosteric inhibition of glycine binding to the GluN1 site . In addition to influencing the pharmacological profile of the NMDA receptor, the identity of the GluN2 subunit co‐assembled with GluN1 is an important determinant of biophysical properties that include sensitivity to block by Mg2+, single‐channel conductance and maximal open probablity and channel deactivation time . Incorporation of the GluN3A subunit into tri‐heteromers containing GluN1 and GluN2 subunits is associated with decreased single‐channel conductance, reduced permeability to Ca2+ and decreased susceptibility to block by Mg2+ . Reduced permeability to Ca2+ has also been observed following the inclusion of GluN3B in tri‐heteromers. The expression of GluN3A, or GluN3B, with GluN1 alone forms, in Xenopus laevis oocytes, a cation channel with unique properties that include activation by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=727 (but not http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4268), lack of permeation by Ca2+ and resistance to blockade by Mg2+ and NMDA receptor antagonists [http://www.ncbi.nlm.nih.gov/pubmed/11823786?dopt=AbstractPlus]. The function of heteromers composed of GluN1 and GluN3A is enhanced by Zn2+, or glycine site antagonists, binding to the GluN1 subunit [http://www.ncbi.nlm.nih.gov/pubmed/18711142?dopt=AbstractPlus]. Zn2+ also directly activates such complexes. The co‐expression of GluN1, GluN3A and GluN3B appears to be required to form glycine‐activated receptors in mammalian cell hosts [http://www.ncbi.nlm.nih.gov/pubmed/17502428?dopt=AbstractPlus].Potency orders unreferenced in the table are from . All nicotinic receptors are pentamers in which each of the five subunits contains four α‐helical transmembrane domains. Genes encoding a total of 17 subunits  have been identified [http://www.ncbi.nlm.nih.gov/pubmed/17651090?dopt=AbstractPlus]. All subunits with the exception of α8 (present in avian species) have been identified in mammals. All α subunits possess two tandem cysteine residues near to the site involved in acetylcholine binding, and subunits not named α lack these residues [http://www.ncbi.nlm.nih.gov/pubmed/18723036?dopt=AbstractPlus]. The orthosteric ligand binding site is formed by residues within at least three peptide domains on the α subunit , and three on the adjacent subunit (complementary component). nAChRs contain several allosteric modulatory sites. One such site, for positive allosteric modulators (PAMs) and allosteric agonists, has been proposed to reside within an intrasubunit cavity between the four transmembrane domains ; see also [http://www.ncbi.nlm.nih.gov/pubmed/21572436?dopt=AbstractPlus]). The high resolution crystal structure of the molluscan acetylcholine binding protein, a structural homologue of the extracellular binding domain of a nicotinic receptor pentamer, in complex with several nicotinic receptor ligands (e.g.[http://www.ncbi.nlm.nih.gov/pubmed/15046723?dopt=AbstractPlus]) and the crystal structure of the extracellular domain of the α1 subunit bound to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3964 at 1.94 Å resolution [http://www.ncbi.nlm.nih.gov/pubmed/17643119?dopt=AbstractPlus], has revealed the orthosteric binding site in detail . Nicotinic receptors at the somatic neuromuscular junction of adult animals have the stoichiometry (α1)2β1δϵ, whereas an extrajunctional (α1)2β1γδ receptor predominates in embryonic and denervated skeletal muscle and other pathological states. Other nicotinic receptors are assembled as combinations of α(2‐6) and β(2‐4) subunits. For α2, α3, α4 and β2 and β4 subunits, pairwise combinations of α and β (e.g. α3β4 and α4β2) are sufficient to form a functional receptor in vitro, but far more complex isoforms may exist in vivo . There is strong evidence that the pairwise assembly of some α and β subunits can occur with variable stoichiometry [e.g. (α4)2(β2)2 or (α4)3(β2)2] which influences the biophysical and pharmacological properties of the receptor [http://www.ncbi.nlm.nih.gov/pubmed/18723036?dopt=AbstractPlus]. α5 and β3 subunits lack function when expressed alone, or pairwise, but participate in the formation of functional hetero‐oligomeric receptors when expressed as a third subunit with another α and β pair  for further examples]. The α6 subunit can form a functional receptor when co‐expressed with β4 in vitro, but more efficient expression ensues from incorporation of a third partner, such as β3 [http://www.ncbi.nlm.nih.gov/pubmed/19498417?dopt=AbstractPlus]. The α7, α8, and α9 subunits form functional homo‐oligomers, but can also combine with a second subunit to constitute a hetero‐oligomeric assembly (e.g. α7β2 and α9α10). For functional expression of the α10 subunit, co‐assembly with α9 is necessary. The latter, along with the α10 subunit, appears to be largely confined to cochlear and vestibular hair cells. Comprehensive listings of nicotinic receptor subunit combinations identified from recombinant expression systems, or in vivo, are given in [http://www.ncbi.nlm.nih.gov/pubmed/18723036?dopt=AbstractPlus]. In addition, numerous proteins interact with nicotinic ACh receptors modifying their assembly, trafficking to and from the cell surface, and activation by ACh .Nicotinic acetylcholine receptors are members of the Cys‐loop family of transmitter‐gated ion channels that includes the GABANC‐IUPHAR has recommended a nomenclature and classification scheme for nicotinic acetylcholine (nACh) receptors based on the subunit composition of known, naturally‐ and/or heterologously‐expressed nACh receptor subtypes [http://www.ncbi.nlm.nih.gov/pubmed/10353988?dopt=AbstractPlus]. Headings for this table reflect abbreviations designating nACh receptor subtypes based on the predominant α subunit contained in that receptor subtype. An asterisk following the indicated α subunit denotes that other subunits are known to, or may, assemble with the indicated α subunit to form the designated nACh receptor subtype(s). Where subunit stoichiometries within a specific nACh receptor subtype are known, numbers of a particular subunit larger than 1 are indicated by a subscript following the subunit .The nicotinic receptor Subcommittee of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5460, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5347, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3967, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5348, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2585 and the natural transmitter, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=294 (ACh). A summary of their profile across differing receptors is provided in [http://www.ncbi.nlm.nih.gov/pubmed/16876883?dopt=AbstractPlus] and quantitative data across numerous assay systems are summarized in [http://www.ncbi.nlm.nih.gov/pubmed/16033252?dopt=AbstractPlus]. Quantitative data presented in the table for commonly used antagonists and channel blockers for human receptors studied under voltage‐clamp are from . Type I PAMs increase peak agonist‐evoked responses but have little, or no, effect on the rate of desensitization of α7 nicotinic ACh receptors whereas type II PAMs also cause a large reduction in desensitization (reviewed in [http://www.ncbi.nlm.nih.gov/pubmed/21575610?dopt=AbstractPlus]).Commonly used agonists of nACh receptors that display limited discrimination in functional assays between receptor subtypes include Neuropharmacology96: 150‐6 https://www.ncbi.nlm.nih.gov/pubmed/25446670?dopt=AbstractPlusAuerbach A. (2015) Agonist activation of a nicotinic acetylcholine receptor. et al. (2015) Therapeutic Potential of α7 Nicotinic Acetylcholine Receptors. Pharmacol. Rev.67: 1025‐73 https://www.ncbi.nlm.nih.gov/pubmed/26419447?dopt=AbstractPlusBertrand D et al. (2018) Nicotinic acetylcholine receptors at the single‐channel level. Br. J. Pharmacol.175: 1789‐1804 https://www.ncbi.nlm.nih.gov/pubmed/28261794?dopt=AbstractPlusBouzat C et al. (2015) Allosteric modulation of nicotinic acetylcholine receptors. Biochem. Pharmacol.97: 408‐417 https://www.ncbi.nlm.nih.gov/pubmed/26231943?dopt=AbstractPlusChatzidaki A et al. (2016) Understanding the Bases of Function and Modulation of α7 Nicotinic Receptors: Implications for Drug Discovery. Mol. Pharmacol.90: 288‐99 https://www.ncbi.nlm.nih.gov/pubmed/27190210?dopt=AbstractPlusCorradi J et al. (2018) Proteins and chemical chaperones involved in neuronal nicotinic receptor expression and function: an update. Br. J. Pharmacol.175: 1869‐1879 https://www.ncbi.nlm.nih.gov/pubmed/28294298?dopt=AbstractPlusCrespi A et al. (2015) Nicotinic ACh receptors as therapeutic targets in CNS disorders. Trends Pharmacol. Sci.36: 96‐108 https://www.ncbi.nlm.nih.gov/pubmed/25639674?dopt=AbstractPlusDineley KT et al. (1999) International Union of Pharmacology. XX. Current status of the nomenclature for nicotinic acetylcholine receptors and their subunits. Pharmacol. Rev.51: 397‐401 https://www.ncbi.nlm.nih.gov/pubmed/10353988?dopt=AbstractPlusLukas RJ et al. (2015) Looking below the surface of nicotinic acetylcholine receptors. Trends Pharmacol. Sci.36: 514‐23 https://www.ncbi.nlm.nih.gov/pubmed/26067101?dopt=AbstractPlusStokes C et al. (2018) Orthosteric and allosteric potentiation of heteromeric neuronal nicotinic acetylcholine receptors. Br. J. Pharmacol.175: 1805‐1821 https://www.ncbi.nlm.nih.gov/pubmed/28199738?dopt=AbstractPlusWang J etal. (2016)Heteromeric α7β2 Nicotinic Acetylcholine Receptors in the Brain. Trends Pharmacol. Sci.37: 562‐574 https://www.ncbi.nlm.nih.gov/pubmed/27179601?dopt=AbstractPlusWu J NC‐IUPHAR Subcommittee on P2X Receptorsnomenclature as agreed by the  ) have a trimeric topology  with two putative TM domains, gating primarily Na+, K+ and Ca2+, exceptionally Cl‐. The Nomenclature Subcommittee has recommended that for P2X receptors, structural criteria should be the initial criteria for nomenclature where possible. X‐ray crystallography indicates that functional P2X receptors are trimeric and three agonist molecules are required to bind to a single receptor in order to activate it . Native receptors may occur as either homotrimers (e.g. P2X1 in smooth muscle) or heterotrimers  may be inhibited by desensitisation using stable agonists (e.g. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4093‐http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4093); http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1728 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1725 are non‐selective antagonists at rat and human P2X1‐3,5 and hP2X4, but not rP2X4,6,7 [http://www.ncbi.nlm.nih.gov/pubmed/8598206?dopt=AbstractPlus], and can also inhibit ATPase activity [http://www.ncbi.nlm.nih.gov/pubmed/7889301?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4225 is inactive at rP2X2, an antagonist at rP2X3 (pIC50 5.6) and enhances agonist responses at rP2X4 [http://www.ncbi.nlm.nih.gov/pubmed/10556935?dopt=AbstractPlus]. Antagonist potency of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4266 at recombinant P2X2, P2X3 and P2X5 is two orders of magnitude lower than that at P2X1 receptors [http://www.ncbi.nlm.nih.gov/pubmed/10193905?dopt=AbstractPlus]. The P2X7 receptor may be inhibited in a non‐competitive manner by the protein kinase inhibitors http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4235 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5953 [http://www.ncbi.nlm.nih.gov/pubmed/15210579?dopt=AbstractPlus], while the p38 MAP kinase inhibitor http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4207 and the cyclic imide http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4142 show a species‐dependent non‐competitive action .Agonists listed show selectivity within recombinant P2X receptors of http://www.ncbi.nlm.nih.gov/pubmed/15778739?dopt=AbstractPlus]. Some recombinant P2X receptors expressed to high density bind http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5406 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5405‐http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5405, although the latter can also bind to 5‐nucleotidase [http://www.ncbi.nlm.nih.gov/pubmed/8548175?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5407 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5408 have been used as high affinity antagonist radioligands for P2X3 (and P2X2/3) and P2X7 receptors, respectively [http://www.ncbi.nlm.nih.gov/pubmed/19558545?dopt=AbstractPlus]. Several high affinity radioligands for the P2X7 receptor have been recently synthesized . http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9540 has shown clinical efficacy in reducing refractory chronic cough [http://www.ncbi.nlm.nih.gov/pubmed/25467586?dopt=AbstractPlus].The pH‐sensitive dye used in culture media, phenol red, is also reported to inhibit P2X1 and P2X3 containing channels . The channel is likely to exist as a homopentamer of 4TM subunits that form an intrinsic cation selective channel equipermeable to Na+, K+ and Cs+, but impermeable to Ca2+ and Mg2+ [http://www.ncbi.nlm.nih.gov/pubmed/26872532?dopt=AbstractPlus]. ZAC displays constitutive activity that can be blocked by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2294 and high concentrations of Ca2+ [http://www.ncbi.nlm.nih.gov/pubmed/26872532?dopt=AbstractPlus]. Although denoted ZAC, the channel is more potently activated by protons and copper, with greater and lesser efficacy than zinc, respectively [http://www.ncbi.nlm.nih.gov/pubmed/26872532?dopt=AbstractPlus]. ZAC is present in the human, chimpanzee, dog, cow and opossum genomes, but is functionally absent from mouse, or rat, genomes .The zinc‐activated channel  by transition metals including Fe2+, Co2+, Ni2+, Cd2+, or Al3+ [http://www.ncbi.nlm.nih.gov/pubmed/26872532?dopt=AbstractPlus]. The concentration response relationship to Cu2+ is biphasic, with concentrations exceeding 30 μM being associated with reduced activation [http://www.ncbi.nlm.nih.gov/pubmed/26872532?dopt=AbstractPlus].The ZAC subunit does not appear to exist in the mouse or rat genomes [et al. (2009) A nomenclature for ligand‐gated ion channels. Neuropharmacology56: 2‐5 https://www.ncbi.nlm.nih.gov/pubmed/18655795?dopt=AbstractPlusCollingridge GL et al. (2016) Zinc as Allosteric Ion Channel Modulator: Ionotropic Receptors as Metalloproteins. Int J Mol Sci17: https://www.ncbi.nlm.nih.gov/pubmed/27384555?dopt=AbstractPlusPeralta FA et al. (2016) Copper and protons directly activate the zinc‐activated channel. Biochem. Pharmacol.103: 109‐17 https://www.ncbi.nlm.nih.gov/pubmed/26872532?dopt=AbstractPlusTrattnig SM http://www.ncbi.nlm.nih.gov/pubmed/16036917?dopt=AbstractPlus]. In addition to their prominence in signal transduction, these ion channels are also among the most common drug targets. As for other large protein superfamilies, understanding the molecular relationships among family members, developing a unified, rational nomenclature for the ion channel families and subfamilies, and assigning physiological functions and pharmacological significance to each family member has been an important challenge.The voltage‐gated ion channels and their structural relatives comprise a superfamily encoded by at least 143 genes in the human genome and are therefore one of the largest superfamilies of signal transduction proteins, following the G proteincoupled receptors and the protein kinases in number [et al. (2005) Introduction to the IUPHAR Compendium of Voltage‐Gated Ion Channels 2005 Pharmacological Reviews57: 385Catterall WA NC‐IUPHARnomenclature as agreed by  [http://www.ncbi.nlm.nih.gov/pubmed/16382101?dopt=AbstractPlus]) are putative 6TM, voltage‐gated, alkalinization‐activated calcium permeant channels that are presumed to assemble as a tetramer of α‐like subunits and mediate the current ICatSper [http://www.ncbi.nlm.nih.gov/pubmed/16467839?dopt=AbstractPlus]. In mammals, CatSper subunits are structurally most closely related to individual domains of voltageactivated calcium channels (Cav) [http://www.ncbi.nlm.nih.gov/pubmed/11595941?dopt=AbstractPlus]. CatSper1 [http://www.ncbi.nlm.nih.gov/pubmed/11595941?dopt=AbstractPlus], CatSper2 [http://www.ncbi.nlm.nih.gov/pubmed/11675491?dopt=AbstractPlus] and CatSpers 3 and 4 , in common with a putative 2TM auxiliary CatSperβ protein [http://www.ncbi.nlm.nih.gov/pubmed/17478420?dopt=AbstractPlus] and two putative 1TM associated CatSperγ and CatSperδ proteins , are restricted to the testis and localised to the principle piece of sperm tail. The novel cross‐species CatSper channel inhibitor, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=10266, has been proposed as a useful tool to aid characterisation of native CatSper channels [http://www.ncbi.nlm.nih.gov/pubmed/29723408?dopt=AbstractPlus].CatSper channels  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 . 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 and(‐/‐)Catsper1 mice [http://www.ncbi.nlm.nih.gov/pubmed/16467839?dopt=AbstractPlus] and also mature human sperm . 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 . 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 . Thus, it is likely that the CatSper pore is formed by a heterotetramer of CatSpers1‐4 [http://www.ncbi.nlm.nih.gov/pubmed/17227845?dopt=AbstractPlus] in association with the auxiliary subunits  that are also essential for function [http://www.ncbi.nlm.nih.gov/pubmed/21224844?dopt=AbstractPlus]. CatSper channels are required for the increase in intracellular Ca2+ concentration in sperm evoked by egg zona pellucida glycoproteins [http://www.ncbi.nlm.nih.gov/pubmed/19211808?dopt=AbstractPlus]. Mouse and human sperm swim against the fluid flow and Ca2+ signaling through CatSper is required for the rheotaxis [http://www.ncbi.nlm.nih.gov/pubmed/23453951?dopt=AbstractPlus]. In vivo, CatSper1‐null spermatozoa cannot ascend the female reproductive tracts efficiently . It has been shown that CatSper channels form four linear Ca2+ signaling domains along the flagella, which orchestrate capacitation‐associated tyrosine phosphorylation [http://www.ncbi.nlm.nih.gov/pubmed/24813608?dopt=AbstractPlus].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 [http://www.ncbi.nlm.nih.gov/pubmed/17460039?dopt=AbstractPlus]. Mouse KSper is encoded by mSlo3, a protein detected only in testis . In human sperm, such alkalinization may result from the activation of Hv1, a proton channel [http://www.ncbi.nlm.nih.gov/pubmed/20679352?dopt=AbstractPlus]. Mutations in CatSpers are associated with syndromic and non‐syndromic male infertility [http://www.ncbi.nlm.nih.gov/pubmed/20648059?dopt=AbstractPlus]. In human ejaculated spermatozoa, progesterone (<50 nM) potentiates the CatSper current by a non‐genomic mechanism and acts synergistically with intracellular alkalinisation [http://www.ncbi.nlm.nih.gov/pubmed/21412339?dopt=AbstractPlus]. Spermcells frominfertile patients witha deletion inCatSper2gene lack ICatSper and the progesterone response [http://www.ncbi.nlm.nih.gov/pubmed/23530196?dopt=AbstractPlus]. In addition, certain prostaglandins  also potentiate CatSper mediated currents .CatSper channel subunits expressed singly, or in combination, fail to functionally express in heterologous expression systems [http://www.ncbi.nlm.nih.gov/pubmed/22354039?dopt=AbstractPlus].In human sperm, CatSper channels are also activated by various small molecules including endocrine disrupting chemicals (EDC) and proposed as a polymodal sensor  (31). The channels are regulated by luminal pH [http://www.ncbi.nlm.nih.gov/pubmed/24776928?dopt=AbstractPlus], PIP2 [http://www.ncbi.nlm.nih.gov/pubmed/23063126?dopt=AbstractPlus], intracellular ATP and extracellular amino acids [http://www.ncbi.nlm.nih.gov/pubmed/23394946?dopt=AbstractPlus]. TPCs are also involved in the NAADP‐activated Ca2+ release from lysosomal Ca2+ stores . Mice lacking TPCs are viable but have phenotypes including compromised lysosomal pH stability, reduced physical endurance [http://www.ncbi.nlm.nih.gov/pubmed/23394946?dopt=AbstractPlus], resistance to Ebola viral infection [http://www.ncbi.nlm.nih.gov/pubmed/25722412?dopt=AbstractPlus] and fatty liver [http://www.ncbi.nlm.nih.gov/pubmed/25144390?dopt=AbstractPlus]. No major human diseaseassociated TPC mutation has been reported.TPCs are the major Naet al. (2005) International Union of Pharmacology. L. Nomenclature and structure‐Kintzer AF et al. (2018) On the structure and mechanism of two‐pore channels. FEBS J.285: 233‐243 function relationships of CatSper and two‐pore channels. Pharmacol. Rev.57: 451‐4 [https://www.ncbi.nlm.nih.gov/pubmed/28656706?dopt=AbstractPlus] [https://www.ncbi.nlm.nih.gov/pubmed/16382101?dopt=AbstractPlus]Clapham DE et al. (2017) Two‐Pore Channels: Catalyzers of Endolysosomal Transport and Function. Front Pharmacol8: 45 [https://www.ncbi.nlm.nih.gov/pubmed/28223936?dopt=AbstractPlus]Grimm C Cyclic nucleotide‐gated (CNG) channels are responsible for signalling in the primary sensory cells of the vertebrate visual and olfactory systems.http://www.ncbi.nlm.nih.gov/pubmed/2578616?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/2481236?dopt=AbstractPlus], where light signals through rhodopsin and transducin to stimulate phosphodiesterase and reduce intracellular http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2347level. This results ina closure ofCNG channels and a reduced ‘dark current’. Similar channels were found in the cilia of olfactory neurons [http://www.ncbi.nlm.nih.gov/pubmed/3027574?dopt=AbstractPlus] and the pineal gland [http://www.ncbi.nlm.nih.gov/pubmed/1719422?dopt=AbstractPlus]. 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.CNG channels arevoltage‐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 [NC‐IUPHAR subcommittee on voltage‐gated ion channelsA standardised nomenclature for CNG and HCN channels has been proposed by the  [http://www.ncbi.nlm.nih.gov/pubmed/16382102?dopt=AbstractPlus].https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:2152 (http://www.uniprot.org/uniprot/Q8IV77), https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:2151 (http://www.uniprot.org/uniprot/Q14028) and https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:2153 (http://www.uniprot.org/uniprot/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 .CNGA1, CNGA2 and CNGA3 express functional channels as homomers. Three additional subunits http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2352 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2347 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 . 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.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 http://www.ncbi.nlm.nih.gov/pubmed/12702747?dopt=AbstractPlus]. High resolution structural studies of CNG and HCN channels has provided insight into the the gating processes of these channels .It is believed that the channels can form heteromers with each other, as has been shown for HCN1 and HCN4  and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2357 [http://www.ncbi.nlm.nih.gov/pubmed/12084770?dopt=AbstractPlus] have proven useful in identifying and studying functional HCN channels in native cells. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2358 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2355 are also useful blocking agents.HCN channels are permeable to both Naet al. (2018) Structural insights into the mechanisms of CNBD channel function. J. Gen. Physiol.150: 225–244 [https://www.ncbi.nlm.nih.gov/pubmed/29233886?dopt=AbstractPlus]James ZM et al. (2018) Retinal Cyclic Nucleotide‐Gated Channels: From Pathophysiology to Ther‐ apy. Int J Mol Sci19: [https://www.ncbi.nlm.nih.gov/pubmed/29518895?dopt=AbstractPlus]Michalakis S 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 [https://www.ncbi.nlm.nih.gov/pubmed/24142069?dopt=AbstractPlus]Podda MV et al. (2017) The Hyperpolarization‐Activated Cyclic Nucleotide‐Gated Channels: from Biophysics to Pharmacology of a Unique Family of Ion Channels. Pharmacol. Rev.69: 354‐395 [https://www.ncbi.nlm.nih.gov/pubmed/28878030?dopt=AbstractPlus]Sartiani L et al. (2014) HCN channels: new roles in sinoatrial node function. Curr Opin Pharmacol15: 83‐90 [https://www.ncbi.nlm.nih.gov/pubmed/24441197?dopt=AbstractPlus]Wahl‐Schott C NC‐IUPHAR subcommittees on potassium channels , which has placed cloned channels into groups based on gene family and structure of channels that exhibit 6, 4 or 2 transmembrane domains (TM).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 asdiverse ascognition, muscle contraction and hormone secretion. Potassium channels aresubdivided 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 riseof intracellular calcium ions orareconstitutively active. A standardised nomenclature for potassium channels has been proposed by the 2+‐ activated Slo subfamily  and the Ca2+and Na+‐activated SK subfamily . As for the 2TM family, the pore‐forming a subunits form tetramers and heteromeric channels may be formed within subfamilies .Calcium‐ and sodium‐ activated potassium channels are members of the 6TM family of K channels which comprises the voltage‐gated KV subfamilies, including the KCNQ subfamily, the EAG subfamily (which includes herg channels), the Caet al. (2018) Calcium‐ and voltage‐gated BK channels in vascular smooth muscle. Pflugers Arch.470: 1271‐1289 [https://www.ncbi.nlm.nih.gov/pubmed/29748711?dopt=AbstractPlus]Dopico AM 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 [https://www.ncbi.nlm.nih.gov/pubmed/28267675?dopt=AbstractPlus]Kaczmarek LK et al. (2018) Physiological Roles and Therapeutic Potential of Ca2+ Activated Potassium Channels in the Nervous System. Front Mol Neurosci11: 258 [https://www.ncbi.nlm.nih.gov/pubmed/30104956?dopt=AbstractPlus]Kshatri AS ir2.x) that are constitutively active, the G‐protein‐activated inward‐rectifier K channels (Kir3.x) and the ATP‐sensitive K channels ). The pore‐forming α subunits form tetramers, and heteromeric channels may be formed within subfamilies (e.g. Kir3.2 with Kir3.3).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 (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, described in the http://www.guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=79, is based on similarities in both structural and functional properties within subfamilies and this explains the “common abbreviation” nomenclature in the tables below.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 K2P6, K2P7.1, K2P15.1and K2P12.1 subtypes, when expressed in isolation, are nonfunctional. All 4TM channels are insensitive to the classical potassium channel blockers http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2343 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2416, but are blocked to varying degrees by Ba2+ ions.The KV subfamilies, the EAG subfamily (which includes hERG channels), the Ca2+‐activated Slo subfamily  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 . The pharmacology largely, reflects the subunit composition of the functional channel.The 6TM family of K channels comprises the voltage‐gated Ket al. (1998) Toward understanding the assembly and structure of KATP channels. Physiol. Rev.78: 227‐45 [https://www.ncbi.nlm.nih.gov/pubmed/9457174?dopt=AbstractPlus]Aguilar‐Bryan L et al. (2015) Targeting two‐pore domain K(+) channels TREK‐1 and TASK‐3 for the treatment of depression: a new therapeutic concept. Br. J. Pharmacol.172: 771‐84 [https://www.ncbi.nlm.nih.gov/pubmed/25263033?dopt=AbstractPlus]Borsotto M et al. (2015) SK channels and ventricular arrhythmias in heart failure. Trends Cardiovasc. Med.25: 508‐14 [https://www.ncbi.nlm.nih.gov/pubmed/25743622?dopt=AbstractPlus]Chang PC et al. (2017) Stretch‐activated potassium currents in the heart: Focus on TREK‐1 and arrhythmias. Prog. Biophys. Mol. Biol.130: 223‐232 [https://www.ncbi.nlm.nih.gov/pubmed/28526352?dopt=AbstractPlus]Decher N et al. (2015) The family of >K2P channels: salient structural and functional properties. J. Physiol. (Lond.)593: 2587‐603 [https://www.ncbi.nlm.nih.gov/pubmed/25530075?dopt=AbstractPlus]Feliciangeli S et al. (2016) KATP Channels in the Cardiovascular System. Physiol. Rev.96: 177‐252Foster MN https://www.ncbi.nlm.nih.gov/pubmed/26660852?dopt=AbstractPlus][et al. (2019) Two‐pore domain potassium channels: emerging targets for novel analgesic drugs: IUPHAR Review 26. Br J Pharmacol176: 256‐266 [https://www.ncbi.nlm.nih.gov/pubmed/30325008?dopt=AbstractPlus]Gada K et al. (2005) International Union of Pharmacology. LV. Nomenclature and molecular relationships of two‐P potassium channels. Pharmacol. Rev.57: 527‐40 [https://www.ncbi.nlm.nih.gov/pubmed/16382106?dopt=AbstractPlus]Goldstein SA et al. (2017) Modulation of Kv7 channels and excitability in the brain. Cell. Mol. Life Sci.Greene DL 74: 495‐508 [https://www.ncbi.nlm.nih.gov/pubmed/27645822?dopt=AbstractPlus]et al. (2003) International Union of Pharmacology. XLI. Compendium of voltage‐gated ion channels: potassium channels. Pharmacol. Rev.55: 583‐6 [https://www.ncbi.nlm.nih.gov/pubmed/14657415?dopt=AbstractPlus]Gutman GA 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 [https://www.ncbi.nlm.nih.gov/pubmed/28267675?dopt=AbstractPlus]Kaczmarek LK et al. (2005) International Union of Pharmacology. LIV. Nomenclature and molecular relationships of inwardly rectifying potassium channels. Pharmacol. Rev.57: 509‐26 [https://www.ncbi.nlm.nih.gov/pubmed/16382105?dopt=AbstractPlus]Kubo Y et al. (2017) Molecular Determinants of BK Channel Functional Diversity and Functioning. Physiol. Rev.97: 39‐87 [https://www.ncbi.nlm.nih.gov/pubmed/27807200?dopt=AbstractPlus]Latorre R et al. (2016) Gating, Regulation, and Structure in >K2P K+ Channels: In Varietate Concordia? Mol. Pharmacol.90: 309‐17 [https://www.ncbi.nlm.nih.gov/pubmed/27268784?dopt=AbstractPlus]Niemeyer MI et al. (2017) Towards understanding the molecular basis of ion channel modulation by lipids: Mechanistic models and current paradigms. Biochim. Biophys. Acta1859: 1507‐1516 [https://www.ncbi.nlm.nih.gov/pubmed/28408206?dopt=AbstractPlus]Poveda JA et al. (2017) G Protein‐Gated Potassium Channels: A Link to Drug Addiction. Trends Pharmacol. Sci.38: 378‐392 [https://www.ncbi.nlm.nih.gov/pubmed/28188005?dopt=AbstractPlus]Rifkin RA et al. (2017) Regulation of KCNQ/Kv7 family voltage‐gated K+ channels by lipids. Biochim. Biophys. Acta1859: 586‐597 [https://www.ncbi.nlm.nih.gov/pubmed/27818172?dopt=AbstractPlus]Taylor KC et al. (2016) Perspectives on the Two‐Pore Domain Potassium Channel TREK‐1 (TWIKRelated K(+) Channel 1). A Novel Therapeutic Target? J. Med. Chem.59: 5149‐57 [https://www.ncbi.nlm.nih.gov/pubmed/26588045?dopt=AbstractPlus]Vivier D et al. (2005) International Union of Pharmacology. LII. Nomenclature and molecular relationships of calcium‐activated potassium channels. Pharmacol. Rev.57: 463‐72 [https://www.ncbi.nlm.nih.gov/pubmed/16382103?dopt=AbstractPlus]Wei AD et al. (2016) Mechanisms contributing to myocardial potassium channel diversity, regulation and remodeling. Trends Cardiovasc. Med.26: 209‐18 [https://www.ncbi.nlm.nih.gov/pubmed/26391345?dopt=AbstractPlus]Yang KC 2+ 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 . In addition to the three mammalian isoforms described below, various nonmammalian isoforms of the ryanodine receptor have been identified [http://www.ncbi.nlm.nih.gov/pubmed/8874493?dopt=AbstractPlus]. The function of the ryanodine receptor channels may also be influenced by closely associated proteins such as the tacrolimus (FK506)‐binding protein, calmodulin [http://www.ncbi.nlm.nih.gov/pubmed/12707260?dopt=AbstractPlus], triadin, calsequestrin, junctin and sorcin, and by protein kinases and phosphatases. Recent studies solving the structure of the ryanodine receptor have shed light on the structural basis of ryanodine receptor function  and Meissner (2017) [http://www.ncbi.nlm.nih.gov/pubmed/29122978?dopt=AbstractPlus]].The ryanodine receptors (RyRs) are found on intracellular 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 .The modulators of channel function included in this table are those most commonly used to identify ryanodine‐sensitive Caet al. (2017) Physiology and Pharmacology of Ryanodine Receptor Calcium Release Channels. Adv. Pharmacol.79: 287‐324 https://www.ncbi.nlm.nih.gov/pubmed/28528672?dopt=AbstractPlusDulhunty AF J. Gen. Physiol.149: 1065‐1089 https://www.ncbi.nlm.nih.gov/pubmed/29122978?dopt=AbstractPlusMeissner G. (2017) The structural basis of ryanodine receptor ion channel function. 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 https://www.ncbi.nlm.nih.gov/pubmed/26009186?dopt=AbstractPlusO'Brien F Protein Sci.26: 52‐68 ), 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 [http://www.ncbi.nlm.nih.gov/pubmed/16460288?dopt=AbstractPlus]). Established, or potential, physiological functions of the individual members of the TRP families are discussed in detail in the recommended reviews and in a number of books . The established, or potential, involvement of TRP channels in disease is reviewed in  and [http://www.ncbi.nlm.nih.gov/pubmed/20127491?dopt=AbstractPlus], together with a special edition of Biochemica et Biophysica Acta on the subject [http://www.ncbi.nlm.nih.gov/pubmed/17368864?dopt=AbstractPlus]. Additional disease related reviews, for pain [http://www.ncbi.nlm.nih.gov/pubmed/28924972?dopt=AbstractPlus], stroke [http://www.ncbi.nlm.nih.gov/pubmed/25502473?dopt=AbstractPlus], sensation and inflammation [http://www.ncbi.nlm.nih.gov/pubmed/25361914?dopt=AbstractPlus], itch [http://www.ncbi.nlm.nih.gov/pubmed/24830011?dopt=AbstractPlus], and airway disease , are available. The pharmacology of most TRP channels has been advanced in recent years. 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. See Rubaiy (2019) for a review of pharmacological tools for TRPC1/C4/C5 channels [http://www.ncbi.nlm.nih.gov/pubmed/30656647?dopt=AbstractPlus]. Most TRP channels are regulated by phosphoinostides such as PtInsP2 although the effects reported are often complex, occasionally contradictory, and likely to be dependent upon experimental conditions, such as intracellular ATP levels . 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.The TRP superfamily of channels (http://www.ncbi.nlm.nih.gov/pubmed/17217068?dopt=AbstractPlus]). TRPA1 activation of sensory neurons contribute to nociception . Pungent chemicals such as mustard oil (AITC), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2419, and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2423 activate TRPA1 by modification of free thiol groups of cysteine side chains, especially those located in its amino terminus . Alkenals with α, β‐unsaturated bonds, such as propenal (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2418), butenal (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6288), and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2417 can react with free thiols via Michael addition and can activate TRPA1. However, potency appears to weaken as carbon chain length increases . Covalent modification leads to sustained activation of TRPA1. Chemicals including http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2497, menthol, and local anesthetics reversibly activate TRPA1 by non‐covalent binding . TRPA1 is not mechanosensitive under physiological conditions, but can be activated by cold temperatures . The electron cryo‐EM structure of TRPA1 [http://www.ncbi.nlm.nih.gov/pubmed/25855297?dopt=AbstractPlus] 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.TRPA1 is the sole mammalian member of this group  . A gain‐of‐function mutation in TRPA1 was found to cause familial episodic pain syndrome [http://www.ncbi.nlm.nih.gov/pubmed/20547126?dopt=AbstractPlus].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 ) 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 . A comprehensive listing of G‐protein coupled receptors that activate TRPC channels is given in [http://www.ncbi.nlm.nih.gov/pubmed/18940894?dopt=AbstractPlus]. Hetero‐oligomeric complexes of TRPC channels and their association with proteins to form signalling complexes are detailed in [http://www.ncbi.nlm.nih.gov/pubmed/17486362?dopt=AbstractPlus] and [http://www.ncbi.nlm.nih.gov/pubmed/17217079?dopt=AbstractPlus]. 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 . 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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2433 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2441 . Activation of TRPC channels by lipids is discussed by [http://www.ncbi.nlm.nih.gov/pubmed/21624095?dopt=AbstractPlus]. Important progress has been recently made in TRPC pharmacology . TRPC channels regulate a variety of physiological functions and are implicated in many human diseases .Members of the TRPC subfamily  fall into the five subgroups outlined below.Members of the TRPM subfamily  exists as multiple splice variants which differ significantly in their biophysical properties. TRPM3 is expressed in somatosensory neurons and may be important in development of heat hyperalgesia during inflammation (see review [http://www.ncbi.nlm.nih.gov/pubmed/28720517?dopt=AbstractPlus]). 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 . TRPM3 may contribute to the detection of noxious heat [http://www.ncbi.nlm.nih.gov/pubmed/21555074?dopt=AbstractPlus].In 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 [2 must also be present (reviewed by [http://www.ncbi.nlm.nih.gov/pubmed/20553742?dopt=AbstractPlus]). Numerous splice variants of TRPM2 exist which differ in their activation mechanisms [http://www.ncbi.nlm.nih.gov/pubmed/19372375?dopt=AbstractPlus]. 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 (adenosine5′‐O‐disphosphoribose phosphate) [http://www.ncbi.nlm.nih.gov/pubmed/25918360?dopt=AbstractPlus]. TRPM2 is involved in warmth sensation [http://www.ncbi.nlm.nih.gov/pubmed/2955270?dopt=AbstractPlus], and contributes to neurological diseases [http://www.ncbi.nlm.nih.gov/pubmed/29671419?dopt=AbstractPlus]. Recent study shows that 2′‐deoxy‐ADPR is an endogenous TRPM2 superagonist [http://www.ncbi.nlm.nih.gov/pubmed/28671679?dopt=AbstractPlus].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, PIP2+ [http://www.ncbi.nlm.nih.gov/pubmed/20716668?dopt=AbstractPlus]. A splice variant of TRPM4 (i.e.TRPM4b) and TRPM5 are molecular candidates for endogenous calcium‐activated cation (CAN) channels [http://www.ncbi.nlm.nih.gov/pubmed/21290294?dopt=AbstractPlus]. TRPM4 is active in the late phase of repolarization of the cardiac ventricular action potential. TRPM4 deletion or knockout enhances beta adrenergic‐mediated inotropy [http://www.ncbi.nlm.nih.gov/pubmed/24226423?dopt=AbstractPlus]. Mutations are associated with conduction defects . TRPM4 has been shown to be an important regulator of Ca2+ entry in to mast cells [http://www.ncbi.nlm.nih.gov/pubmed/17217063?dopt=AbstractPlus] and dendritic cell migration [http://www.ncbi.nlm.nih.gov/pubmed/18758465?dopt=AbstractPlus]. TRPM5 in taste receptor cells of the tongue appears essential for the transduction of sweet, amino acid and bitter stimuli [http://www.ncbi.nlm.nih.gov/pubmed/17217064?dopt=AbstractPlus] TRPM5 contributes to the slow afterdepolarization of layer 5 neurons in mouse prefrontal cortex [http://www.ncbi.nlm.nih.gov/pubmed/25237295?dopt=AbstractPlus]. Both TRPM4 and TRPM5 are required transduction of taste stimuli [http://www.ncbi.nlm.nih.gov/pubmed/29311301?dopt=AbstractPlus].TRPM4 and TRPM5 have the distinction within all TRP channels of being impermeable to 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. TRPM7 is responsible for oxidant‐ induced Zn2+ release from intracellular vesicles [http://www.ncbi.nlm.nih.gov/pubmed/28696294?dopt=AbstractPlus] and contributes to intestinal mineral absorption essential for postnatal survival [http://www.ncbi.nlm.nih.gov/pubmed/30770447?dopt=AbstractPlus].TRPM6 and 7 combine channel and enzymatic activities (’chanzymes’). These channels have the unusual property of permeation by divalent . TRPML channels are probably restricted to intracellular vesicles and mutations in the gene (MCOLN1) encoding TRPML1 (mucolipin‐1) cause 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, fission from late endosome‐lysosome hybrid vesicles and lysosomal exocytosis [http://www.ncbi.nlm.nih.gov/pubmed/23993788?dopt=AbstractPlus]. TRPML2 and TRPML3 show increased channel activity in low extracellular sodium and are activated by similar small molecules [http://www.ncbi.nlm.nih.gov/pubmed/22753890?dopt=AbstractPlus]. A naturally occurring gain of function mutation in TRPML3 (i.e. A419P) results in the varitint waddler (Va) mouse phenotype .The TRPML family . Data for wild type TRPML3 are also tabulated . It should be noted that alternative methodologies, particularly in the case of TRPML1, have resulted in channels with differing biophysical characteristics (reviewed by [http://www.ncbi.nlm.nih.gov/pubmed/19158345?dopt=AbstractPlus]). Initial functional characteristics of TRPML channels are performed on their Va mutations of TRPMLs at loci equivalent to TRPML3 A419P. Current pharmacological characterization of channel activators and blockers are conducted on wild‐type channel proteins using endolysosomal patch‐clamp .Data in the table are for TRPML proteins mutated  or PKD2 family is comprised of PKD2 (PC2), PKD2L1 (PC2L1), PKD2L2 (PC2L2), which have been renamed TRPP1, TRPP2 and TRPP3, respectively [http://www.ncbi.nlm.nih.gov/pubmed/20716668?dopt=AbstractPlus]. It should also be noted that the nomenclature of PC2 was TRPP2 in old literature. However, PC2 has been uniformed to be called TRPP2 [http://www.ncbi.nlm.nih.gov/pubmed/29149325?dopt=AbstractPlus]. PKD2 family channels are clearly distinct from the PKD1 family, whose function is unknown. PKD1 and PKD2 form a hetero‐oligomeric complex with a 1:3 ratio. [http://www.ncbi.nlm.nih.gov/pubmed/30093605?dopt=AbstractPlus]. Although still being sorted out, TRPP family members appear to be 6TM spanning nonselective cation channels.The TRPP family  can broadly be divided into the non‐selective cation channels, TRPV1‐4 and the more calcium selective channels TRPV5 and TRPV6.Members of the TRPV family . 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 [http://www.ncbi.nlm.nih.gov/pubmed/20515731?dopt=AbstractPlus]. The pharmacology of TRPV1 channels is discussed in detail in [http://www.ncbi.nlm.nih.gov/pubmed/19063991?dopt=AbstractPlus] and [http://www.ncbi.nlm.nih.gov/pubmed/19297520?dopt=AbstractPlus]. TRPV2 is probably not a thermosensor in man [http://www.ncbi.nlm.nih.gov/pubmed/21832173?dopt=AbstractPlus], but has recently been implicated in innate immunity [http://www.ncbi.nlm.nih.gov/pubmed/20118928?dopt=AbstractPlus]. 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 .TRPV1 is involved in the development of thermal hyperalgesia following inflammation and may contribute to the detection of noxius heat .TRPV5 and TRPV6 are highly expressed in placenta, bone, and kidney. Under physiological conditions, TRPV5 and TRPV6 are calcium selective channels involved in the absorption and reabsorption of calcium across intestinal and kidney tubule epithelia . 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. Different TRPV4 mutations load to a broad spectrum of dominant skeletal dysplasias  and spinal muscular atrophies and hereditary motor and sensory neuropathies . Similar mutations were also found in patients with Charcot‐Marie‐Tooth disease type 2C [http://www.ncbi.nlm.nih.gov/pubmed/20037586?dopt=AbstractPlus]. 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.Activation of TRPV1 by depolarisation is strongly temperature‐dependent via a channel opening rate that increases with increasing temperature. The Vet al. (2017) Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists. Med Res Rev37: 936‐983 https://www.ncbi.nlm.nih.gov/pubmed/27976413?dopt=AbstractPlusAghazadeh Tabrizi M et al. (2017) Transient Receptor Potential Channels in neuropathic pain. Curr Opin Pharmacol32: 9‐15 https://www.ncbi.nlm.nih.gov/pubmed/27835802?dopt=AbstractPlusBasso L et al. (2017) Lipids as central modulators of sensory TRP channels. Biochim. Biophys. Acta1859: 1615‐1628  and NC‐IUPHAR Subcommittee on Ca2+ channelsapproved by the [http://www.ncbi.nlm.nih.gov/pubmed/16382099?dopt=AbstractPlus]. 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  channels; (2) the highvoltage activated dihydropyridine‐insensitive (CaV2.x) channels and (3) the low‐voltage‐activated  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–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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5483 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5484.Calcium (Cahttp://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2536) has been approved for the treatment of chronic pain [http://www.ncbi.nlm.nih.gov/pubmed/18518786?dopt=AbstractPlus].In many cell types, P and Q current components cannot be adequately separated and many researchers in the field have adopted the terminology ‘P/Q‐type’ current when referring to either component. Both of these physiologically defined current types are conducted by alternative forms of Cav2.1. Ziconotide  International Union of Pharmacology. XLVIII. Nomenclature and structure‐function relationships of voltage‐gated calcium channels. Pharmacol. Rev.57: 411–25 [https://www.ncbi.nlm.nih.gov/pubmed/16382099?dopt=AbstractPlus]Catterall WA et al. (2015) Structural basis for pharmacology of voltage‐gated sodium and calcium channels. Mol. Pharmacol.88: 141–50 [https://www.ncbi.nlm.nih.gov/pubmed/25848093?dopt=AbstractPlus]Catterall WA et al. (2015) Deciphering voltage‐gated Na(+) and Ca(2+) channels by studying prokaryotic ancestors. Trends Biochem. Sci.40: 526–34 [https://www.ncbi.nlm.nih.gov/pubmed/26254514?dopt=AbstractPlus]Catterall WA Brain Neurosci Adv2: [https://www.ncbi.nlm.nih.gov/pubmed/30320224?dopt=AbstractPlus]Dolphin AC. (2018) Voltage‐gated calcium channels: their discovery, function and importance as drug targets. et al. (2017) How and why are calcium currents curtailed in the skeletal muscle voltagegated calcium channels? J. Physiol. (Lond.)595: 1451–1463 [https://www.ncbi.nlm.nih.gov/pubmed/27896815?dopt=AbstractPlus]Flucher BE et al. (2017) Regulation of voltage gated calcium channels by GPCRs and post‐translational modification. Curr Opin Pharmacol32: 1–8 [https://www.ncbi.nlm.nih.gov/pubmed/27768908?dopt=AbstractPlus]Huang J et al. (2018) Calcium Channels, Synaptic Plasticity, and Neuropsychiatric Disease. Neuron98: 466–481 [https://www.ncbi.nlm.nih.gov/pubmed/29723500?dopt=AbstractPlus]Nanou E et al. (2016) L‐type calcium channels as drug targets in CNS disorders. Channels (Austin)10: 7–13 [https://www.ncbi.nlm.nih.gov/pubmed/26039257?dopt=AbstractPlus]Ortner NJ et al. (2016) Cardiac voltage‐gated calcium channel macromolecular complexes. Biochim. Biophys. Acta1863: 1806–12 [https://www.ncbi.nlm.nih.gov/pubmed/26707467?dopt=AbstractPlus]Rougier JS Nat Rev Drug Discov15: 19–34 [https://www.ncbi.nlm.nih.gov/pubmed/26542451?dopt=AbstractPlus]Zamponi GW. (2016) Targeting voltage‐gated calcium channels in neurological and psychiatric diseases. et al. (2015) The Physiology, Pathology, and Pharmacology of Voltage‐Gated Calcium Channels and Their Future Therapeutic Potential. Pharmacol. Rev.67: 821–70 [https://www.ncbi.nlm.nih.gov/pubmed/26362469?dopt=AbstractPlus]Zamponi GW http://www.ncbi.nlm.nih.gov/pubmed/20961760?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/18463791?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/18801839?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/16554753?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/16556803?dopt=AbstractPlus]. 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 . Proton flux through Hv1 is instead most likely mediated by a water wire completed in a crevice of the protein whenthe voltage‐sensing S4 helix moves in response to a change in transmembrane potential . Hv1 expresses largely as a dimer mediated by intracellular C‐terminal coiled‐coil interactions [http://www.ncbi.nlm.nih.gov/pubmed/20147290?dopt=AbstractPlus] but individual promoters nonetheless support gated H+ flux via separate conduction pathways . 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 .The voltage‐gated proton channel  is a putative 4TM proton‐selective channel gated by membrane depolarization and which is sensitive to the transmembrane pH gradient . Phosphorylation of Hv1 within the N‐terminal domain by PKC enhances the gating of the channel [http://www.ncbi.nlm.nih.gov/pubmed/20037153?dopt=AbstractPlus]. Tabulated IC50 values for Zn2+ and Cd2+ are for heterologously expressed human and mouse Hv1 . Zn2+ is not a conventional pore blocker, but is coordinated by two, or more, external protonation sites involving http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1204 residues [http://www.ncbi.nlm.nih.gov/pubmed/16554753?dopt=AbstractPlus]. Zn2+ binding may occur at the dimer interface between pairs of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1204 residues from both monomers where it may interfere with channel opening [http://www.ncbi.nlm.nih.gov/pubmed/20231140?dopt=AbstractPlus]. Mouse knockout studies demonstrate that Hv1 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 [http://www.ncbi.nlm.nih.gov/pubmed/19372380?dopt=AbstractPlus]. Additional physiological functions of Hv1 are reviewed by [http://www.ncbi.nlm.nih.gov/pubmed/20961760?dopt=AbstractPlus].The voltage threshold  Voltage‐gated proton (H(v)1) channels, a singular voltage sensing domain. FEBS Lett.589: 3471–8 [https://www.ncbi.nlm.nih.gov/pubmed/26296320?dopt=AbstractPlus]Castillo K Proc. Natl. Acad. Sci. U.S.A.115: 9057–9059 [https://www.ncbi.nlm.nih.gov/pubmed/30135099?dopt=AbstractPlus]DeCoursey TE. (2018) Gating currents indicate complex gating of voltage‐gated proton channels. J R Soc Interface15: [https://www.ncbi.nlm.nih.gov/pubmed/29643227?dopt=AbstractPlus]DeCoursey TE. (2018) Voltage and pH sensing by the voltage‐gated proton channel, HV1. et al. (2016) Pharmacological Modulation of Proton Channel Hv1 in Cancer Therapy: Future Perspectives. Mol. Pharmacol.90: 385–402 [https://www.ncbi.nlm.nih.gov/pubmed/27260771?dopt=AbstractPlus]Fernández A et al. (2015) Gating mechanisms of voltage‐gated proton channels. Annu. Rev. Biochem.84: 685–709 [https://www.ncbi.nlm.nih.gov/pubmed/26034892?dopt=AbstractPlus]Okamura Y http://www.ncbi.nlm.nih.gov/pubmed/11486343?dopt=AbstractPlus]. 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 [http://www.ncbi.nlm.nih.gov/pubmed/21743477?dopt=AbstractPlus]. 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 [http://www.ncbi.nlm.nih.gov/pubmed/21743477?dopt=AbstractPlus]. Auxiliary β1, β2, β3 and β4 subunits consist of a large extracellular N‐terminal domain, a single transmembrane segment and a shorter cytoplasmic domain.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  NC‐IUPHAR Subcommittee on sodium channels  .http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2616  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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2405.Sodium channels are also blocked by local anaesthetic agents, antiarrythmic drugs and antiepileptic drugs. In general, these drugs are not highly selective among channel subtypes. There are two clear functional fingerprints for distinguishing different subtypes. These are sensitivity to et al. (2005) International Union of Pharmacology. XLVII. Nomenclature and structure‐function relationships of voltage‐gated sodium channels. Pharmacol. Rev.57: 397409 [https://www.ncbi.nlm.nih.gov/pubmed/16382098?dopt=AbstractPlus]Catterall WA et al. (2017) The chemical basis for electrical signaling. Nat. Chem. Biol.13: 455–463 [https://www.ncbi.nlm.nih.gov/pubmed/28406893?dopt=AbstractPlus]Catterall WA et al. (2017) The pharmacology of voltage‐gated sodium channel activators. Neuropharmacology127: 87–108 [https://www.ncbi.nlm.nih.gov/pubmed/28416444?dopt=AbstractPlus]Deuis JR et al. (2018) Structural basis for gating pore current in periodic paralysis. Nature557: 590–594 [https://www.ncbi.nlm.nih.gov/pubmed/29769724?dopt=AbstractPlus]Jiang D et al. (2016) Voltage‐gated sodium channels and pain‐related disorders. Clin. Sci.130: 2257–2265 [https://www.ncbi.nlm.nih.gov/pubmed/27815510?dopt=AbstractPlus]Kanellopoulos AH et al. (2018) Structural basis for the modulation of voltage‐gated sodium channels by animal toxins. Science362: [https://www.ncbi.nlm.nih.gov/pubmed/30049784?dopt=AbstractPlus]Shen H et al. (2018) Post‐translational dysfunctions in channelopathies of the nervous system. Neuropharmacology132: 31–42 [https://www.ncbi.nlm.nih.gov/pubmed/28571716?dopt=AbstractPlus]Terragni B A number of ion channels in the human genome do not fit readily into the classification of either ligand‐gated or voltage‐gated ion channels. These are identified below.http://www.ncbi.nlm.nih.gov/pubmed/26342685?dopt=AbstractPlus]. Since the isolation and cloning of the first aquaporin (AQP1)[http://www.ncbi.nlm.nih.gov/pubmed/1373524?dopt=AbstractPlus], 12 additional mammalian membersof thefamily havebeenidentified, although little is known about the functional properties of one of these  and it is thus not tabulated. The other 12 aquaporins can be broadly divided into three families: orthodox aquaporins  permeable mainly to water, but for some additional solutes [http://www.ncbi.nlm.nih.gov/pubmed/24090884?dopt=AbstractPlus]; aquaglyceroporins , additionally permeableto glycerol and for some isoforms urea [http://www.ncbi.nlm.nih.gov/pubmed/26365508?dopt=AbstractPlus], and superaquaporins (AQP11 and 12) located within cells [http://www.ncbi.nlm.nih.gov/pubmed/24189537?dopt=AbstractPlus]. Some aquaporins also conduct ammonia and/or H2O2 giving rise to the terms ’ammoniaporins’ (’aquaammoniaporins’) and ’peroxiporins’, respectively. Aquaporins are impermeable to protons and other inorganic and organic cations, with the possible exception of AQP1 [http://www.ncbi.nlm.nih.gov/pubmed/26365508?dopt=AbstractPlus]. One or more members of this family of proteins have been found to be expressed in almost all tissues of the body [reviewed in Yang (2017) [1104]]. AQPs are involved in numerous processes that include systemic water homeostasis, adipocyte metabolism, brain oedema, cell migration and fluid secretion by epithelia and loss of function mutations of some human AQPs, or their disruption by autoantibodies further underscore their importance [reviewed by Verkman et al. (2014) [http://www.ncbi.nlm.nih.gov/pubmed/24625825?dopt=AbstractPlus], Kitchen et al. (2105) [http://www.ncbi.nlm.nih.gov/pubmed/26365508?dopt=AbstractPlus]].Aquaporins and aquaglyceroporins are membrane channels that allow the permeation of water and certain other small solutes across the cell membrane, or in the case of AQP6, AQP11 and AQP12A, intracellular membranes, such as vesicles and the endoplasmic reticulum membrane [http://www.ncbi.nlm.nih.gov/pubmed/26342685?dopt=AbstractPlus]. In addition to the four pores contributed by the protomers, an additional hydrophobic pore exists within the center of the complex [http://www.ncbi.nlm.nih.gov/pubmed/26342685?dopt=AbstractPlus] that may mediate the transport of gases  and cations  by some AQPs . Although numerous small molecule inhibitors of aquaporins, particularly APQ1, have been reported primarily from Xenopus oocyte swelling assays, the activity of most has subsequently been disputed upon retesting using assays of water transport that are less prone to various artifacts [http://www.ncbi.nlm.nih.gov/pubmed/26993802?dopt=AbstractPlus] and they are therefore excluded from the tables [see Tradtrantip et al. (2017) [http://www.ncbi.nlm.nih.gov/pubmed/28258578?dopt=AbstractPlus] for a review].Functional AQPs exist as homotetramers that are the water conducting units wherein individual AQP subunits (each a protomer) have six transmembrane helices and two half helices that constitute a seventh ’pseudotransmembrane domain’ that surrounds a narrow water conducting channel [Proc Am Thorac Soc3: 5–13 [https://www.ncbi.nlm.nih.gov/pubmed/16493146?dopt=AbstractPlus]Agre P. (2006) The aquaporin water channels. et al. (2002) Aquaporin water channels–from atomic structure to clinical medicine. J. Physiol. (Lond.)542: 3–16 [https://www.ncbi.nlm.nih.gov/pubmed/12096044?dopt=AbstractPlus]Agre P et al. (2015) Challenges and achievements in the therapeutic modulation of aquaporin functionality. Pharmacol. Ther.155: 22–35 [https://www.ncbi.nlm.nih.gov/pubmed/26277280?dopt=AbstractPlus]Beitz E et al. (2009) Discovery of the aquaporins and development of the field. Handb Exp Pharmacol 3–28 [https://www.ncbi.nlm.nih.gov/pubmed/19096770?dopt=AbstractPlus]Carbrey JM et al. (2017) Transport Characteristics of Aquaporins. Adv. Exp. Med. Biol.969: 51–62 [https://www.ncbi.nlm.nih.gov/pubmed/28258565?dopt=AbstractPlus]Geng X et al. (2009) Aquaporin water channels in mammals. Clin. Exp. Nephrol.13: 107–17 [https://www.ncbi.nlm.nih.gov/pubmed/19085041?dopt=AbstractPlus]Ishibashi K et al. (2015) Beyond water homeostasis: Diverse functional roles of mammalian aquaporins. Biochim. Biophys. Acta1850: 2410–21 [https://www.ncbi.nlm.nih.gov/pubmed/26365508?dopt=AbstractPlus]Kitchen P et al. (2018) Aquaporins as Targets of Dietary Bioactive Phytocompounds. Front Mol Biosci5: 30 [https://www.ncbi.nlm.nih.gov/pubmed/29721498?dopt=AbstractPlus]Tesse A et al. (2017) Aquaporin‐Targeted Therapeutics: State‐of‐the‐Field. Adv. Exp. Med. Biol.969: 239–250 [https://www.ncbi.nlm.nih.gov/pubmed/28258578?dopt=AbstractPlus]Tradtrantip L InAdvancesin ExperimentalMedicineandBiology Edited by Yang B:Springer: 1–276 [ISBN: 9789402410570]Yang B.(2017) Aquaporins http://www.ncbi.nlm.nih.gov/pubmed/19827947?dopt=AbstractPlus]). Excluding the transmittergated GABAA and glycine receptors (see separate tables), well characterised chloride channels can be classified as certain members of the voltage‐sensitive ClC subfamily, calcium‐activated channels, high (maxi) conductance channels, the cystic fibrosis transmembrane conductance regulator (CFTR) and volume regulated channels [http://www.ncbi.nlm.nih.gov/pubmed/19153558?dopt=AbstractPlus]. No official recommendation exists regarding the classification of chloride channels. Functional chloride channels that have been cloned from, or characterised within, mammalian tissues are listed with the exception of several classes of intracellular channels (e.g. CLIC) that are reviewed by in [http://www.ncbi.nlm.nih.gov/pubmed/20100480?dopt=AbstractPlus].Chloride channels are a functionally and structurally diverse group of anion selective channels involved in processes including the regulation of the excitability of neurones, skeletal, cardiac and smooth muscle, cell volume regulation, transepithelial salt transport, the acidification of internal and extracellular compartments, the cell cycle and apoptosis  contains 9 members that fall, on the basis of sequence homology, into three groups; ClC‐1, ClC‐2, hClC‐Ka (rClC‐K1) and hClC‐Kb (rClC‐K2); ClC‐3 to ClC‐5, and ClC‐6 and ‐7. ClC‐1 and ClC‐2 are plasma membrane chloride channels. ClC‐Ka and ClC‐Kb are also plasma membrane channels (largely expressed in the kidney and inner ear) when associated with barttin , a 320 amino acid 2TM protein [http://www.ncbi.nlm.nih.gov/pubmed/11734858?dopt=AbstractPlus]. The localisation of the remaining members of the ClC family is likely to be predominantly intracellular in vivo, although they may traffic to the plasma membrane in overexpression systems. Numerous recent reports indicate that ClC‐4, ClC‐5, ClC‐6 and ClC‐7 (and by inference ClC‐3) function as Cl‐/H+ antiporters (secondary active transport), rather than classical Cl− channels ; reviewed in ). It has recently been reported that the activity of ClC‐5 as a Cl‐/H+ exchanger is important for renal endocytosis [http://www.ncbi.nlm.nih.gov/pubmed/20430975?dopt=AbstractPlus]. Alternative splicing increases the structural diversity within the ClC family. The crystal structure of two bacterial ClC proteins has been described [http://www.ncbi.nlm.nih.gov/pubmed/11796999?dopt=AbstractPlus] and a eukaryotic ClC transporter (CmCLC) has recently been described at 3.5 Å resolution [http://www.ncbi.nlm.nih.gov/pubmed/20929736?dopt=AbstractPlus]. Each ClC subunit, with a complex topology of 18 intramembrane segments, contributes a single pore to a dimeric ‘double‐barrelled’ ClC channel that contains two independently gatedpores, confirming the predictions of previous functional and structural investigations . As found for ClC‐4, ClC‐5, ClC‐6 and ClC‐7, the prokaryotic ClC homologue (ClC‐ec1) and CmCLC function as H+/Cl antiporters, rather than as ion channels . The generation of monomers from dimeric ClC‐ec1 has firmly established that each ClC subunit is afunctional unit fortransport and thatcross‐subunit interaction is not required for Cl‐/H+ exchange in ClC transporters [http://www.ncbi.nlm.nih.gov/pubmed/21048711?dopt=AbstractPlus].The mammalian ClC family . ClC‐1 has significant opening probability at resting membrane potential, accounting for 75% of the membrane conductance at rest in skeletal muscle, and is important for stabilization of the membrane potential. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4098, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4113 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2439 act intracellularly and exhibit a strongly voltage‐dependent block with strong inhibition at negative voltages and relief of block at depolarized potentials ([http://www.ncbi.nlm.nih.gov/pubmed/17128287?dopt=AbstractPlus] and reviewed in [http://www.ncbi.nlm.nih.gov/pubmed/12512775?dopt=AbstractPlus]). Inhibition of ClC‐2 by the peptide http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4199, from Leiurus quinquestriatus herbareus venom, is likely to occur through inhibition of channel gating, rather than direct open channel blockade [http://www.ncbi.nlm.nih.gov/pubmed/19574231?dopt=AbstractPlus]. Although ClC‐2 can be activated by cell swelling, it does not correspond to the VRAC channel (see below). Alternative potential physiological functions for ClC‐2 are reviewed in [http://www.ncbi.nlm.nih.gov/pubmed/19708126?dopt=AbstractPlus]. Functional expression of human ClC‐Ka and ClC‐Kb requires the presence of barttin  reviewed in [http://www.ncbi.nlm.nih.gov/pubmed/21423394?dopt=AbstractPlus]. The properties of ClC‐Ka/barttin and ClC‐Kb/barttin tabulated are those observed in mammalian expression systems: in oocytes the channels display time‐ and voltage‐dependent gating. The rodent homologue (ClC‐K1) of ClC‐Ka demonstrates limited expression as a homomer, but its function is enhanced by barttin which increases both channel opening probablility in the physiological range of potentials  reviewed in [http://www.ncbi.nlm.nih.gov/pubmed/21423394?dopt=AbstractPlus]). ClC‐Ka is approximately 5 to 6‐fold more sensitive to block by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4104 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4177 than ClC‐Kb, while newly synthesized benzofuran derivatives showed the same blocking affinity (<10 μM) on both CLC‐K isoforms [http://www.ncbi.nlm.nih.gov/pubmed/18216243?dopt=AbstractPlus]. The biophysical and pharmacological properties of ClC‐3, and the relationship of the protein to the endogenous volume‐regulated anion channel(s) VRAC  are controversial and further complicated by the possibility that ClC‐3 may function as both a Cl‐/H+ exchanger and an ion channel . The functional properties tabulated are those most consistent with the close structural relationship between ClC‐3, ClC‐4 and ClC‐5. Activation of heterologously expressed ClC‐3 by cell swelling in response to hypotonic solutions is disputed, as are many other aspects of its regulation. Dependent upon the predominant extracellular anion (e.g. SCN− versus Cl‐), CIC‐4 can operate in two transport modes: a slippage mode in which behaves as an ion channel and an exchanger mode in which unitary transport rate is 10‐fold lower [http://www.ncbi.nlm.nih.gov/pubmed/19364886?dopt=AbstractPlus]. Similar findings have been made for ClC‐5 [http://www.ncbi.nlm.nih.gov/pubmed/18063579?dopt=AbstractPlus]. ClC‐7 associates with a β subunit, Ostm1, which increases the stability of the former [http://www.ncbi.nlm.nih.gov/pubmed/16525474?dopt=AbstractPlus] and is essential for its function [http://www.ncbi.nlm.nih.gov/pubmed/21527911?dopt=AbstractPlus].ClC channels display the permeability sequence Cl− channel involved in normal fluid transport across various epithelia. Of the 1700 mutations identified in CFTR, the most common is the deletion mutant F508 (a class 2 mutation) which results in impaired trafficking of CFTR and reduces its incorporation into the plasma membrane causing cystic fibrosis (reviewed in [http://www.ncbi.nlm.nih.gov/pubmed/21108631?dopt=AbstractPlus]). Channels carrying the F508 mutation that do traffic to the plasma membrane demonstrate gating defects. Thus, pharmacological restoration of the function of the ΔF508 mutant would require a compound that embodies ’corrector’ (i.e. facilitates folding and trafficking to the cell surface) and ’potentiator’ (i.e. promotes opening of channels at the cell surface) activities [http://www.ncbi.nlm.nih.gov/pubmed/21108631?dopt=AbstractPlus]. In addition to acting as an anion channel per se, CFTR may act as a regulator of several other conductances including inhibition of the epithelial Na channel (ENaC), calcium activated chloride channels (CaCC) and volume regulated anion channel (VRAC), activation of the outwardly rectifying chloride channel (ORCC), and enhancementof the sulphonylurea sensitivity of therenalouter medullary potassium channel (ROMK2), (reviewed in [http://www.ncbi.nlm.nih.gov/pubmed/12558550?dopt=AbstractPlus]). CFTR also regulates TRPV4, which provides the Ca2+ signal for regulatory volume decrease in airway epithelia [http://www.ncbi.nlm.nih.gov/pubmed/15489228?dopt=AbstractPlus]. The activities of CFTR and the chloride‐bicarbonate exchangers SLC26A3 (DRA) and SLC26A6 (PAT1) are mutually enhanced by a physical association between the regulatory (R) domain of CFTR and the STAS domain of the SCL26 transporters, an effect facilitated by PKA‐mediated phosphorylation of the R domain of CFTR [http://www.ncbi.nlm.nih.gov/pubmed/15048129?dopt=AbstractPlus].CFTR, a 12TM, ABC transporter‐type protein, is a cAMP‐regulated epithelial cell membrane Clhttp://www.ncbi.nlm.nih.gov/pubmed/20829696?dopt=AbstractPlus]). Corrector compounds that aid the folding of DF508CFTR to increase the amount of protein expressed and potentially delivered to the cell surface include VX‐532 , http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4340, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4234, Corr‐3a and Corr‐4a see [http://www.ncbi.nlm.nih.gov/pubmed/19153558?dopt=AbstractPlus] for details and structures of Corr3a and Corr‐4a). Inhibition of CFTR by intracellular application of the peptide http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4198, from Leiurus quinquestriatus herbareus venom, occurs preferentially for the closed state of the channel [http://www.ncbi.nlm.nih.gov/pubmed/17951250?dopt=AbstractPlus]. CFTR contains two cytoplasmic nucleotide binding domains (NBDs) that bind http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713. A single open‐closing cycle is hypothesised to involve, in sequence: binding of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713 at the Nterminal NBD1, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713 binding to the C‐terminal NBD2 leading to the formation of an intramolecular NBD1‐NBD2 dimer associated with the open state, and subsequent http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713 hydrolysis at NBD2 facilitating dissociation of the dimer and channel closing, and the initiation of a new gating cycle . Phosphorylation by PKA at sites within a cytoplasmic regulatory (R) domain facilitates the interaction of the two NBD domains. PKC  positively regulate CFTR activity.In addition to the agents listed in the table, the novel small molecule, ataluren, induces translational read through of nonsense mutations in CFTR  consisting of 10 members  has been identified and there is firm evidence that some of these members form chloride channels . TMEM16A  produces Ca2+‐activated Cl− currents with kinetics similar to native CaCC currents recorded from different cell types . Knockdown of TMEM16A greatly reduces currents mediated by calcium‐activated chloride channels in submandibular gland cells [http://www.ncbi.nlm.nih.gov/pubmed/18724360?dopt=AbstractPlus] and smooth muscle cells from pulmonary artery [http://www.ncbi.nlm.nih.gov/pubmed/20421283?dopt=AbstractPlus]. In TMEM16A(‐/‐) mice secretion of Ca2+‐dependent Cl− secretion by several epithelia is reduced . Alternative splicing regulates the voltage‐ and Ca2+‐ dependence of TMEM16A and such processing may be tissue‐specific manner and thus contribute to functional diversity [http://www.ncbi.nlm.nih.gov/pubmed/19819874?dopt=AbstractPlus]. There are also reports that TMEM16B  supports CaCC activity (e.g.[http://www.ncbi.nlm.nih.gov/pubmed/19475416?dopt=AbstractPlus]) and in TMEM16B(‐/‐) mice Ca‐activated Cl− currents in the main olfactory epithelium (MOE) and in the vomeronasal organ are virtually absent [http://www.ncbi.nlm.nih.gov/pubmed/21516098?dopt=AbstractPlus].Chloride channels activated by intracellular calcium (CaCC) are widely expressed in excitable and non‐excitable cells where they perform diverse functions . Extracellular http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2439; http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4173 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4113 (but not http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4177) exert a complex effect upon ICl(Ca) in vascular smooth muscle, enhancing and inhibiting inwardly and outwardly directed currents in a manner dependent upon [Ca2+]i (see [http://www.ncbi.nlm.nih.gov/pubmed/16091780?dopt=AbstractPlus] for summary). Considerable crossover in pharmacology with large conductance Ca2+‐activated K+ channels also exists (see [http://www.ncbi.nlm.nih.gov/pubmed/17150263?dopt=AbstractPlus] for overview). Two novel compounds, CaCCinh‐A01 and CaCCinh‐B01 have recently been identified as blockers of calcium‐activated chloride channels in T84 human intestinal epithelial cells [http://www.ncbi.nlm.nih.gov/pubmed/18083779?dopt=AbstractPlus] for structures). Significantly, other novel compounds totally block currents mediated by TMEM116A, but have only a modest effect upon total current mediated by CaCC native to T84 cells or human bronchial epithelial cells, suggesting that TMEM16A is not the predominant CaCC in such cells [http://www.ncbi.nlm.nih.gov/pubmed/21084298?dopt=AbstractPlus]. CaMKII modulates CaCC in a tissue dependent manner . CaMKII inhibitors block activation of ICl(Ca) in T84 cells but have no effect in parotid acinar cells. In tracheal and arterial smooth muscle cells, but not portal vein myocytes, inhibition of CaMKII reduces inactivation of ICl(Ca). Intracellular http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4224 may act as an endogenous negative regulator of CaCC channels activated by Ca2+, or CaMKII. Smooth muscle CaCC are also regulated positively by Ca2+‐dependent phosphatase, calcineurin (see [http://www.ncbi.nlm.nih.gov/pubmed/16091780?dopt=AbstractPlus] for summary).Blockade of I‐ channels are high conductance, anion selective, channels initially characterised in skeletal muscle and subsequently found in many cell types including neurones, glia, cardiac muscle, lymphocytes, secreting and absorbing epithelia, macula densa cells of the kidney and human placenta syncytiotrophoblasts [http://www.ncbi.nlm.nih.gov/pubmed/19340557?dopt=AbstractPlus]. The physiological significance of the maxi Cl‐ channel is uncertain, but roles in cell volume regulation and apoptosis have been claimed. Evidence suggests a role for maxi Clchannels as a conductive pathway in the swelling‐induced release of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713 from mouse mammary C127i cells that may be important for autocrine and paracrine signalling by purines . A similar channel mediates http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713 release from macula densa cells within the thick ascending of the loop of Henle in response to changes in luminal NaCl concentration [http://www.ncbi.nlm.nih.gov/pubmed/12655045?dopt=AbstractPlus]. A family of human high conductance Cl‐ channels (TTYH1‐3) that resemble Maxi Cl‐ channels has been cloned [http://www.ncbi.nlm.nih.gov/pubmed/15010458?dopt=AbstractPlus], but alternatively, Maxi Cl‐ channels have also been suggested to correspond to the voltage‐dependent anion channel, VDAC, expressed at the plasma membrane .Maxi Clhttp://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2391 (and cis‐unsaturated fatty acids) is voltageindependent, occurs at an intracellular site, and involves both channel shut down (Kd = 4‐5 μM) and a reduction of γ (Kd = 1314 μM). Blockade of channel activity by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4314, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4177, Gd3+ and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2391 is paralleled by decreased swelling‐induced release of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713 . Channel activation by anti‐oestrogens in whole cell recordings requires the presence of intracellular nucleotides and is prevented by pre‐treatment with http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1013, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5485, or intracellular dialysis with GDPβS [http://www.ncbi.nlm.nih.gov/pubmed/11579158?dopt=AbstractPlus]. Activation by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1016 is suppressed by low concentrations of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5349, suggesting that a dephosphorylation event by protein phosphatase PP2A occurs in the activation pathway [http://www.ncbi.nlm.nih.gov/pubmed/11579158?dopt=AbstractPlus]. In contrast, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1013 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1016 appear to directly inhibit the maxi Cl‐ channel of human placenta reconstituted into giant liposomes and recorded in excised patches [http://www.ncbi.nlm.nih.gov/pubmed/19604577?dopt=AbstractPlus].Differing ionic conditions may contribute to variable estimates of γ reported in the literature. Inhibition by ‐ transport, angiogenesis, cell proliferation, necrosis, apoptosis, glutamate release from astrocytes, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5012  release from pancreatic β cells and resistance to the anti‐cancer drug, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5343 . VRAC may not be a single entity, but may instead represent a number of different channels that are expressed to a variable extent in different tissues and are differentially activated by cell swelling. In addition to ClC‐3 expression products (see above) several former VRAC candidates including MDR1 (ABCB1 P‐glycoprotein), Icln, Band 3 anion exchanger and phospholemman are also no longer considered likely to fulfil this function .Volume activated chloride channels  participate in regulatory volumedecrease(RVD) inresponse tocell swelling. VRAC may also be important for several other processes including the regulation of membrane excitability, transcellular ClIn addition to conducting monovalent anions, in many cell types the activation of VRAC by a hypotonic stimulus can allow the efflux of organic osmolytes such as amino acids and polyols that may contribute to RVD.http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2352‐activated Cl‐ channel that does not correspond to CFTR has been described in intestinal Paneth cells [http://www.ncbi.nlm.nih.gov/pubmed/9769420?dopt=AbstractPlus]. A Cl channel activated by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2347 with a dependence on raised intracellular Ca2+ has been recorded in various vascular smooth muscle cells types, which has a pharmacology and biophysical characteristics very different from the ‘conventional’ CaCC . It has been proposed that http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5377  is an essential component of the http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2347‐activated channel [http://www.ncbi.nlm.nih.gov/pubmed/18776041?dopt=AbstractPlus]. A proton‐activated, outwardly rectifying anion channel has also been described [http://www.ncbi.nlm.nih.gov/pubmed/15961423?dopt=AbstractPlus].In addition to some intracellular chloride channels that are not considered here, plasma membrane channels other than those listed have been functionally described. Many cells and tissues contain outwardly rectifying chloride channels (ORCC) that may correspond to VRAC active under isotonic conditions. A et al. (2015) Potential role of cardiac chloride channels and transporters as novel therapeutic targets. Pharmacol. Ther.145: 67–75 [https://www.ncbi.nlm.nih.gov/pubmed/25160469?dopt=AbstractPlus]Adkins GB et al. (2012) International Union of Basic and Clinical Pharmacology. LXXXV: calciumactivated chloride channels. Pharmacol. Rev.64: 1–15 [https://www.ncbi.nlm.nih.gov/pubmed/22090471?dopt=AbstractPlus]Huang F J. Cell. Physiol.233: 787–798 [https://www.ncbi.nlm.nih.gov/pubmed/28121009?dopt=AbstractPlus]KamaleddinMA.(2018)Molecular, biophysical, and pharmacological properties of calcium‐activated chloride channels. Trends Biochem. Sci.40: 535–43 [https://www.ncbi.nlm.nih.gov/pubmed/26254230?dopt=AbstractPlus]Kunzelmann K. (2015) TMEM16, LRRC8A, bestrophin: chloride channels controlled by Ca(2+) and cell volume. et al. (2016) Biophysics and Physiology of the Volume‐Regulated Anion Channel (VRAC)/Volume‐Sensitive Outwardly Rectifying Anion Channel (VSOR). Pflugers Arch.468: 371–83 [https://www.ncbi.nlm.nih.gov/pubmed/26739710?dopt=AbstractPlus]Pedersen SF et al. (2015) Chloride channels in cancer: Focus on chloride intracellular channel 1 and 4 (CLIC1 AND CLIC4) proteins in tumor development and as novel therapeutic targets. Biochim. Biophys. Acta1848: 2523–31 [https://www.ncbi.nlm.nih.gov/pubmed/25546839?dopt=AbstractPlus]Peretti M et al. (2016) The properties, functions, and pathophysiology of maxi‐anion channels. Pflugers Arch.468: 405–20 [https://www.ncbi.nlm.nih.gov/pubmed/26733413?dopt=AbstractPlus]Sabirov RZ et al. (2017) CFTR pharmacology. Cell. Mol. Life Sci.74: 117–128 [https://www.ncbi.nlm.nih.gov/pubmed/27704174?dopt=AbstractPlus]Zegarra‐Moran O http://www.ncbi.nlm.nih.gov/pubmed/14597722?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15217338?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12126230?dopt=AbstractPlus]. Gap junction channels allow the passive diffusion of molecules of up to 1,000 Daltons which can include nutrients, metabolites and second messengers (such as IP3) as well as cations and anions. 21 connexin genes and 3 pannexin genes which are structurally related to the invertebrate innexin genes) code for gap junction proteins in humans. Each connexin gap junction comprises 2 hemichannels or ’connexons’ which are themselves formed from 6 connexin molecules. The various connexins have been observed to combine into both homomeric and heteromeric combinations, each of which may exhibit different functional properties. Itis also suggested that individual hemichannels formed by a number of different connexins might be functional in at least some cells [http://www.ncbi.nlm.nih.gov/pubmed/17507078?dopt=AbstractPlus]. Connexins have a common topology, with four α‐helical transmembrane domains, two extracellular loops, a cytoplasmic loop, and N‐ and C‐termini located on the cytoplasmic membrane face. In mice, the most abundant connexins in electrical synapses in the brain seem to be Cx36, Cx45 and Cx57 [http://www.ncbi.nlm.nih.gov/pubmed/15738956?dopt=AbstractPlus]. Mutations in connexin genes are associated with the occurrence of a number of pathologies, such as peripheral neuropathies, cardiovascular diseases and hereditary deafness. The pannexin genes Px1 and Px2 are widely expressed in the mammalian brain [http://www.ncbi.nlm.nih.gov/pubmed/16143426?dopt=AbstractPlus]. Like the connexins, at least some of the pannexins can form hemichannels .Gap junctions are essential for many physiological processes including cardiac and smooth muscle contraction, regulation of neuronal excitability and epithelial electrolyte transport [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4151 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2447 [http://www.ncbi.nlm.nih.gov/pubmed/16216217?dopt=AbstractPlus]. At least some pannexin hemichannels are more sensitive to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4151 than connexins but much less sensitive to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2447 [http://www.ncbi.nlm.nih.gov/pubmed/15715654?dopt=AbstractPlus]. It has been suggested that 2‐aminoethoxydiphenyl borate (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2433) may be a more effective blocker of some connexin channel subtypes  compared to others .Connexins are most commonly named according to their molecular weights, so, for example, Cx23 is the connexin protein of 23 kDa. This can cause confusion when comparing between species – for example, the mouse connexin Cx57 is orthologous to the human connexin Cx62. No natural toxin or specific inhibitor of junctional channels has been identified yet however two compounds often used experimentally to block connexins are et al. (2015) Connexin and pannexin signaling pathways, an architectural blueprint for CNS physiology and pathology? Cell. Mol. Life Sci.72: 2823–51 [https://www.ncbi.nlm.nih.gov/pubmed/26118660?dopt=AbstractPlus]Decrock E et al. (2016) Next‐Generation Connexin and Pannexin Cell Biology. Trends Cell Biol.26: 944–955 [https://www.ncbi.nlm.nih.gov/pubmed/27339936?dopt=AbstractPlus]Esseltine JL et al. (2016) Expression and role of connexin‐based gap junctions in pulmonary inflammatory diseases. Pharmacol. Ther.164: 105–19 [https://www.ncbi.nlm.nih.gov/pubmed/27126473?dopt=AbstractPlus]Freund‐Michel V J. Gen. Physiol.150: 1606–1639 [https://www.ncbi.nlm.nih.gov/pubmed/30389716?dopt=AbstractPlus]Harris AL. (2018) Electrical coupling and its channels. et al. (2015) Regulation of pannexin and connexin channels and their functional role in skeletal muscles. Cell. Mol. Life Sci.72: 2929–35 [https://www.ncbi.nlm.nih.gov/pubmed/26084874?dopt=AbstractPlus]Sáez JC et al. (2017) Inhibitors of connexin and pannexin channels as potential therapeutics. Pharmacol. Ther.180: 144–160 [https://www.ncbi.nlm.nih.gov/pubmed/28720428?dopt=AbstractPlus]Willebrords J http://www.ncbi.nlm.nih.gov/pubmed/27743844?dopt=AbstractPlus]. Piezo channels play a critical role in sensory neuron transduction Piezo proteins are the pore‐forming subunits of trimeric mechanosensitive ion channels that open in response to mechanical stimuli such as shear stress and membrane stretch, allowing positively charged ions, including calcium, to flow into the cell. Piezo orthologs have thus far been identified in numerous eukaryotes. Most vertebrates have two channel isoforms, Piezol and Piezo2. Across species, Piezos are very large proteins  with numerous (>14) predicted transmembrane (TM) domains per subunit and, strikingly, no homology to other known proteins .et al. (2018) Portraits of a pressure sensor. Elife7: [https://www.ncbi.nlm.nih.gov/pubmed/29376828?dopt=AbstractPlus]Chesler AT Science362: 398–399 [https://www.ncbi.nlm.nih.gov/pubmed/30361358?dopt=AbstractPlus]Ehmke H. (2018) The mechanotransduction of blood pressure. etal. (2012)Piezo1: propertiesof a cation selective mechanical channel. Channels(Austin)6: 214–9 [https://www.ncbi.nlm.nih.gov/pubmed/22790400?dopt=AbstractPlus]Gottlieb PAet al. (2017) Piezo channels. Curr. Biol.27: R250‐R252 [https://www.ncbi.nlm.nih.gov/pubmed/28376327?dopt=AbstractPlus]Parpaite T et al. (2015) Piezo channels: from structure to function. Pflugers Arch.467: 95–9 [https://www.ncbi.nlm.nih.gov/pubmed/25037583?dopt=AbstractPlus]Volkers L et al. (2017) Touch, Tension, and Transduction ‐ The Function and Regulation of Piezo Ion Channels. Trends Biochem. Sci.42: 57–71 [https://www.ncbi.nlm.nih.gov/pubmed/27743844?dopt=AbstractPlus]Wu J etal. (2018)PIEZOs mediate neuronal sensing of blood pressure and the baroreceptor reflex. Science362: 464–467 [https://www.ncbi.nlm.nih.gov/pubmed/30361375?dopt=AbstractPlus]Zeng WZ NC‐IUPHAR tentatively recommends the nomenclature NaVi2.1, W.A. Catterall, personal communication) is structurally a member of the family of voltage‐gated sodium channel family (Nav1.1‐Nav1.9) . In contrast to the latter, NaVi2.1, is voltage‐insensitive (denoted in the subscript ’vi’ in the tentative nomenclature) and possesses distinctive ion selectivity and pharmacological properties. NaVi2.1, which is insensitive to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2616 (10 μM), has been proposed to mediate the http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2616‐resistant and voltage‐insensitive Na+ leak current (IL‐Na) observed in many types of neurone [http://www.ncbi.nlm.nih.gov/pubmed/17448995?dopt=AbstractPlus]. However, whether NaVi2.1 is constitutively active has been challenged [http://www.ncbi.nlm.nih.gov/pubmed/19575010?dopt=AbstractPlus]. NaVi2.1 is widely distributed within the central nervous system and is also expressed in the heart and pancreas specifically, in rodents, within the islets of Langerhans . Recently, NaVi2.1 has been proposed to be a core effector for the action of inhibitory G proteins [http://www.ncbi.nlm.nih.gov/pubmed/30556810?dopt=AbstractPlus].The sodium leak channel, non selective , neurotensin  and M3 muscarinic acetylcholine receptors (in MIN6 pancreatic β‐cells) and in a manner that is independent of signalling through G proteins . Pharmacological and molecular biological evidence indicates such modulation to occur though a pathway that involves the activation of Src family tyrosine kinases. It is suggested that NaVi2.1 exists as a macromolecular complex with M3 receptors [http://www.ncbi.nlm.nih.gov/pubmed/19575010?dopt=AbstractPlus] and peptide receptors [http://www.ncbi.nlm.nih.gov/pubmed/19092807?dopt=AbstractPlus], in the latter instance in association with the protein UNC‐80, which recruits Src to the channel complex . By contrast, stimulation of NaVi2.1 by decreased extracellular Ca2+ concentration is G protein dependent and involves a Ca2+‐sensing G protein‐coupled receptor and UNC80 which links NaVi2.1 to the protein UNC79 in the same complex [http://www.ncbi.nlm.nih.gov/pubmed/21040849?dopt=AbstractPlus]. NaVi2.1 null mutant mice have severe disturbances in respiratory rhythm and die within 24 hours of birth [http://www.ncbi.nlm.nih.gov/pubmed/17448995?dopt=AbstractPlus]. NaVi2.1 heterozygous knockout mice display increased serum sodium concentrations in comparison to wildtype littermates and a role for the channel in osmoregulation has been postulated [http://www.ncbi.nlm.nih.gov/pubmed/21177381?dopt=AbstractPlus].In native and recombinant expression systems Naet al. (2014) The sodium leak channel, NALCN, in health and disease. Front Cell Neurosci8: 132 [https://www.ncbi.nlm.nih.gov/pubmed/24904279?dopt=AbstractPlus]Cochet‐Bissuel M et al. (2012) NALCN: a regulator of pacemaker activity. Mol. Neurobiol. 45: 415‐23 [https://www.ncbi.nlm.nih.gov/pubmed/22476981?dopt=AbstractPlus]Lu TZ et al. (2018) G_i/o protein‐coupled receptors in dopamine neurons inhibit the sodium leak channel NALCN. Elife7: [https://www.ncbi.nlm.nih.gov/pubmed/30556810?dopt=AbstractPlus]Philippart F et al. (2014) Regulating excitability of peripheral afferents: emerging ion channel targets. Nat. Neurosci. 17: 153‐63 [https://www.ncbi.nlm.nih.gov/pubmed/24473263?dopt=AbstractPlus]Waxman SG