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 (reviewed in [17]). Excluding the transmittergated GABA_A 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 [80]. 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 [21].

The mammalian ClC family (reviewed in [2,12,17,19,33]) 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 (ENSG00000162399), a 320 amino acid 2TM protein [22]. 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 [28,39,50,59,71]; reviewed in [2,64]). It has recently been reported that the activity of ClC-5 as a Cl^-/H⁺ exchanger is important for renal endocytosis [52]. Alternative splicing increases the structural diversity within the ClC family. The crystal structure of two bacterial ClC proteins has been described [20] and a eukaryotic ClC transporter (CmCLC) has recently been described at 3.5 Å resolution [24]. 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 gated pores, confirming the predictions of previous functional and structural investigations (reviewed in [12,19,33,64]). 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 [1,24]. The generation of monomers from dimeric ClC-ec1 has firmly established that each ClC subunit is a functional unit for transport and that cross-subunit interaction is not required for Cl^-/H⁺ exchange in ClC transporters [66].

ClC channels display the permeability sequence Cl^- > Br^- > I^- (at physiological pH). 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. S-(-)CPP, 9-A-C and niflumic acid act intracellularly and exhibit a strongly voltage-dependent block with strong inhibition at negative voltages and relief of block at depolarized potentials ([40] and reviewed in [63]). Inhibition of ClC-2 by the peptide GaTx2, from Leiurus quinquestriatus herbareus venom, is likely to occur through inhibition of channel gating, rather than direct open channel blockade [78]. 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 [62]. Functional expression of human ClC-Ka and ClC-Kb requires the presence of barttin [22,72] reviewed in [23]. 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 [22,26,72] reviewed in [23]). ClC-Ka is approximately 5 to 6-fold more sensitive to block by 3-phenyl-CPP and DIDS than ClC-Kb, while newly synthesized benzofuran derivatives showed the same blocking affinity (<10 µM) on both CLC-K isoforms [41]. The biophysical and pharmacological properties of ClC-3, and the relationship of the protein to the endogenous volume-regulated anion channel(s) VRAC [3,30] are controversial and further complicated by the possibility that ClC-3 may function as both a Cl^-/H⁺ exchanger and an ion channel [3,59,81]. 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 [4]. Similar findings have been made for ClC-5 [83]. ClC-7 associates with a β subunit, Ostm1, which increases the stability of the former [37] and is essential for its function [39].

CFTR, a 12TM, ABC transporter-type protein, is a cAMP-regulated epithelial cell membrane Cl^- channel involved in normal fluid transport across various epithelia. Of the 1700 mutations identified in CFTR, the most common is the deletion mutant ΔF508 (a class 2 mutation) which results in impaired trafficking of CFTR and reduces its incorporation into the plasma membrane causing cystic fibrosis (reviewed in [13]). Channels carrying the ΔF508 mutation that do traffic to the plasma membrane demonstrate gating defects. Thus, pharmacological restoration 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 [13]. 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 enhancement of the sulphonylurea sensitivity of the renal outer medullary potassium channel (ROMK2), (reviewed in [51]). CFTR also regulates TRPV4, which provides the Ca²⁺ signal for regulatory volume decrease in airway epithelia [6]. 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 [34].

In addition to the agents listed in the table, the novel small molecule, ataluren, induces translational read through of nonsense mutations in CFTR (reviewed in [75]). 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 (which is also a potentiator), VRT-325, KM11060, Corr-3a and Corr-4a see [80] for details and structures of Corr-3a and Corr-4a). Inhibition of CFTR by intracellular application of the peptide GaTx1, from Leiurus quinquestriatus herbareus venom, occurs preferentially for the closed state of the channel [27]. CFTR contains two cytoplasmic nucleotide binding domains (NBDs) that bind ATP. A single open-closing cycle is hypothesised to involve, in sequence: binding of ATP at the N-terminal NBD1, ATP binding to the C-terminal NBD2 leading to the formation of an intramolecular NBD1-NBD2 dimer associated with the open state, and subsequent ATP hydrolysis at NBD2 facilitating dissociation of the dimer and channel closing, and the initiation of a new gating cycle [5,47]. Phosphorylation by PKA at sites within a cytoplasmic regulatory (R) domain facilitates the interaction of the two NBD domains. PKC (and PKGII within intestinal epithelial cells via guanylinstimulated cGMP formation) positively regulate CFTR activity.

Chloride channels activated by intracellular calcium (CaCC) are widely expressed in excitable and non-excitable cells where they perform diverse functions [31]. The molecular nature of CaCC has been uncertain with both CLCA, TWEETY and BEST genes having been considered as likely candidates [17,32,42]. It is now accepted that CLCA expression products are unlikely to form channels per se and probably function as cell adhesion proteins, or are secreted [58]. Similarly, TWEETY gene products do not recapictulate the properties of endogenous CaCC. The bestrophins encoded by genes BEST1-4 have a topology more consistent with ion channels [32] and form chloride channels that are activated by physiological concentrations of Ca²⁺, but whether such activation is direct is not known [32]. However, currents generated by bestrophin over-expression do not resemble native CaCC currents. The evidence for and against bestrophin proteins forming CaCC is critically reviewed by Duran et al. in their 2010 paper [17]. Recently, a new gene family, TMEM16 (anoctamin) consisting of 10 members (TMEM16A-K; anoctamin 1–10) has been identified and there is firm evidence that some of these members form chloride channels [16,35]. TMEM16A (anoctamin 1; Ano 1) produces Ca²⁺-activated Cl^- currents with kinetics similar to native CaCC currents recorded from different cell types [11,67,73,82]. Knockdown of TMEM16A greatly reduces currents mediated by calcium-activated chloride channels in submandibular gland cells [82] and smooth muscle cells from pulmonary artery [43]. In TMEM16A^(-/-) mice secretion of Ca²⁺-dependent Cl^- secretion by several epithelia is reduced [57,67]. Alternative splicing regulates the voltage- and Ca²⁺- dependence of TMEM16A and such processing may be tissue-specific manner and thus contribute to functional diversity [25]. There are also reports that TMEM16B (anoctamin 2; Ano 2) supports CaCC activity (e.g.[60]) and in TMEM16B^(-/-) mice Ca-activated Cl- currents in the main olfactory epithelium (MOE) and in the vomeronasal organ are virtually absent[10] .

Blockade of I_Cl(Ca) by niflumic acid, DIDS and 9-A-C is voltage-dependent whereas block by NPPB is voltage-independent [31]. Extracellular niflumic acid; DCDPC and 9-A-C (but not DIDS) exert a complex effect upon I_Cl(Ca) in vascular smooth muscle, enhancing and inhibiting inwardly and outwardly directed currents in a manner dependent upon [Ca²⁺]_i (see [38] for summary). Considerable crossover in pharmacology with large conductance Ca²⁺-activated K⁺ channels also exists (see [29] for overview). Two novel compounds, CaCC_inh-A01 and CaCC_inh-B01 have recently been identified as blockers of calcium-activated chloride channels in T84 human intestinal epithelial cells [14] 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 [49]. CaMKII modulates CaCC in a tissue dependent manner (reviewed by [31,38]). CaMKII inhibitors block activation of I_Cl(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 I_Cl(Ca). Intracellular Ins(3,4,5,6)P₄ 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 [38] for summary).

Maxi Cl^- 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 [69]. 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 Cl^- channels as a conductive pathway in the swelling-induced release of ATP from mouse mammary C127i cells that may be important for autocrine and paracrine signalling by purines [18,68]. A similar channel mediates ATP release from macula densa cells within the thick ascending of the loop of Henle in response to changes in luminal NaCl concentration [8]. A family of human high conductance Cl^- channels (TTYH1-3) that resemble Maxi Cl^- channels has been cloned [77], but alternatively, Maxi Cl^- channels have also been suggested to correspond to the voltage-dependent anion channel, VDAC, expressed at the plasma membrane [7,53].

Differing ionic conditions may contribute to variable estimates of γ reported in the literature. Inhibition by arachidonic acid (and cis-unsaturated fatty acids) is voltage-independent, occurs at an intracellular site, and involves both channel shut down (K_d = 4–5 µM) and a reduction of γ (K_d = 13–14 µM). Blockade of channel activity by SITS, DIDS, Gd³⁺ and arachidonic acid is paralleled by decreased swelling-induced release of ATP [18,68]. Channel activation by anti-oestrogens in whole cell recordings requires the presence of intracellular nucleotides and is prevented by pre-treatment with 17β-estradiol, dibutyryl cAMP, or intracellular dialysis with GDPβS [15]. Activation by tamoxifen is suppressed by low concentrations of okadaic acid, suggesting that a dephosphorylation event by protein phosphatase PP2A occurs in the activation pathway [15]. In contrast, 17β-estradiol and tamoxifen appear to directly inhibit the maxi Cl^- channel of human placenta reconstituted into giant liposomes and recorded in excised patches [65].

Volume activated chloride channels (also termed VSOAC, volume-sensitive organic osmolyte/anion channel; VRC, volume regulated channel and VSOR, volume expansion-sensing outwardly rectifying anion channel) participate in regulatory volume decrease (RVD) in response to cell swelling. VRAC may also be important for several other processes including the regulation of membrane excitability, transcellular Cl^- transport, angiogenesis, cell proliferation, necrosis, apoptosis, glutamate release from astrocytes, insulin release from pancreatic β cells and resistance to the anti-cancer drug, cisplatin (reviewed by [9,48,51,54]). 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 P-glycoprotein, Icln, Band 3 anion exchanger and phospholemman are also no longer considered likely to fulfil this function (see reviews [51,70]).

In 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.

Other chloride channels
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 cAMP-activated Cl^- channel that does not correspond to CFTR has been described in intestinal Paneth cells [79]. A Cl channel activated by cGMP 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 [44,61]. It has been proposed that bestrophin-3 is an essential component of the cGMP-activated channel [45]. A proton-activated, outwardly rectifying anion channel has also been described [36].

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