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ClC family C

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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The mammalian ClC family (reviewed in [2,5-7,15]) 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 [9]. 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 [13,17,21,25,30]; reviewed in [2,28]). It has recently been reported that the activity of ClC-5 as a Cl-/H+ exchanger is important for renal endocytosis [22]. Alternative splicing increases the structural diversity within the ClC family. The crystal structure of two bacterial ClC proteins has been described [8] and a eukaryotic ClC transporter (CmCLC) has recently been described at 3.5 Å resolution [11]. 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 [5,7,15,28]). 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 [1,11]. 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 [29].

Channels and Subunits

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ClC-1 C Show summary »

ClC-2 C Show summary » More detailed page go icon to follow link

ClC-Ka C Show summary »

ClC-Kb C Show summary »

ClC-3 C Show summary »

ClC-4 C Show summary »


Target Id 703
Nomenclature ClC-4
Previous and unofficial names CLC4 | chloride channel 4 | chloride channel 4-2 | chloride transporter ClC-4 | Clcn4-2 | H(+)/Cl(-) exchange transporter 4 | Clc4-2 | Clcn4 | chloride channel, voltage-sensitive 4 | chloride channel
Genes CLCN4 (Hs), Clcn4 (Mm), Clcn4 (Rn)
Ensembl ID ENSG00000073464 (Hs), ENSMUSG00000000605 (Mm), ENSRNOG00000003533 (Rn)
UniProtKB AC P51793 (Hs), Q61418 (Mm), P51794 (Rn)
Channel blockers
Zn2+ pIC50 4.3 [24]
Cd2+ pIC50 4.2 [24]
Functional characteristics Cl-/H+ antiporter (2Cl-:1H+) [4,25,30]; extreme outward rectification; voltage-dependent gating with midpoint of activation at +73 mV [23]; rapid activation and deactivation; inhibited by extracellular acidosis; non-hydrolytic nucleotide binding required for full activity

ClC-5 C Show summary »

ClC-6 C Show summary »

ClC-7 C Show summary »

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How to cite this family page

Database page citation:

ClC family. Accessed on 20/09/2021. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=128.

Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Mathie A, Peters JA, Veale EL, Striessnig J, Kelly E, Armstrong JF, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Davies JA; CGTP Collaborators. (2019) The Concise Guide to PHARMACOLOGY 2019/20: Ion channels. Br J Pharmacol. 176 Issue S1: S142-228.