Chloride channels

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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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 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 [83]. 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].

ClC family

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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 (BSND, Q8WZ55), 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 [28,39,50,60,72]; reviewed in [2,65]). 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 [12,19,33,65]). 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 [67].

Subunits

ClC-1 Show summary »

ClC-2 Show summary » More detailed page

ClC-Ka Show summary »

ClC-Kb Show summary »

ClC-3 Show summary »

ClC-4 Show summary »

ClC-5 Show summary »

ClC-6 Show summary »

ClC-7 Show summary »

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CFTR

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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].

Channels

CFTR Show summary » More detailed page

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Calcium activated chloride channel

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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 [11,68,74,85]. Knockdown of TMEM16A greatly reduces currents mediated by calcium-activated chloride channels in submandibular gland cells [85] and smooth muscle cells from pulmonary artery [43]. In TMEM16A(-/-) mice secretion of Ca2+-dependent Cl- secretion by several epithelia is reduced [57,68]. 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.[61]) and in TMEM16B(-/-) mice Ca-activated Cl- currents in the main olfactory epithelium (MOE) and in the vomeronasal organ are virtually absent[10] .

Subunits

CaCC Show summary »

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Maxi chloride channel

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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 [70]. 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 [18,69]. 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 [79], 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].

Channels

Maxi Cl- Show summary »

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Volume regulated chloride channels

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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 (INS, P01308) 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 [51,71]).

Channels

VRAC Show summary »

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