Chloride channel ClC-7 (IPR002249)

Short name: Cl_channel-7

Overlapping homologous superfamilies

Family relationships


Chloride channels (CLCs) constitute an evolutionarily well-conserved family of voltage-gated channels that are structurally unrelated to the other known voltage-gated channels. They are found in organisms ranging from bacteria to yeasts and plants, and also to animals. Their functions in higher animals likely include the regulation of cell volume, control of electrical excitability and trans-epithelial transport [PMID: 9046241].

The first member of the family (CLC-0) was expression-cloned from the electric organ of Torpedo marmorata [PMID: 2174129], and subsequently nine CLC-like proteins have been cloned from mammals. They are thought to function as multimers of two or more identical or homologous subunits, and they have varying tissue distributions and functional properties. To date, CLC-0, CLC-1, CLC-2, CLC-4 and CLC-5 have been demonstrated to form functional Cl- channels; whether the remaining isoforms do so is either contested or unproven. One possible explanation for the difficulty in expressing activatable Cl- channels is that some of the isoforms may function as Cl- channels of intracellular compartments, rather than of the plasma membrane. However, they are all thought to have a similar transmembrane (TM) topology, initial hydropathy analysis suggesting 13 hydrophobic stretches long enough to form putative TM domains [PMID: 2174129]. Recently, the postulated TM topology has been revised, and it now seems likely that the CLCs have 10 (or possibly 12) TM domains, with both N- and C-termini residing in the cytoplasm [PMID: 9207144].

A number of human disease-causing mutations have been identified in the genes encoding CLCs. Mutations in CLCN1, the gene encoding CLC-1, the major skeletal muscle Cl- channel, lead to both recessively and dominantly-inherited forms of muscle stiffness or myotonia [PMID: 7581380]. Similarly, mutations in CLCN5, which encodes CLC-5, a renal Cl- channel, lead to several forms of inherited kidney stone disease [PMID: 8559248]. These mutations have been demonstrated to reduce or abolish CLC function.

CLC-7 is a CLC that, together with CLC-6, forms a distinct branch of the CLC gene family. CLC-7 consists of 789 amino acid residues (human isoform) and is ~45% identical to CLC-6 (at the amino acid level). CLC-7 is broadly expressed, but, to date, functional studies have not generated measurable Cl- currents; its identification as a functional Cl- channel therefore remains putative. Interestingly, CLC-7 is the only known eukaryotic CLC protein to lack a highly conserved glycosylation site between hydrophobic domains D8 and D9 [PMID: 8543009].

GO terms

Biological Process

GO:0006821 chloride transport

Molecular Function

GO:0005247 voltage-gated chloride channel activity

Cellular Component

GO:0016020 membrane

Contributing signatures

Signatures from InterPro member databases are used to construct an entry.