InterPro domain: IPR002251

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 [ 1 ].

The first member of the family (CLC-0) was expression-cloned from the electric organ of Torpedo marmorata [ 2 ], 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 [ 3 ]. 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 [ 3 ].

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 [ 4 ]. Similarly, mutations in CLCN5, which encodes CLC-5, a renal Cl- channel, lead to several forms of inherited kidney stone disease [ 5 ]. These mutations have been demonstrated to reduce or abolish CLC function.

In plants, chloride channels contribute to a number of plant-specificfunctions, such as regulation of turgor, stomatal movement, nutrienttransport and metal tolerance. By contrast with Cl ^- channels in animal cells, they are also responsible for the generation of action potentials.The best documented examples are the chloride channels of guard cells,which control opening and closing of stomata. Recently, four homologousproteins that belong to the CLC family have been cloned from Arabidopsis thaliana (Mouse-ear cress) [ 6 ]. Hydropathy analysis suggests that they havea similar membrane topology to other CLC proteins, with up to 12 TM domains.Expression in Xenopus oocytes failed to generate measurable Cl ^- currents,although protein analysis suggested they had been synthesised and insertedinto cell membranes. However, similar CLC proteins have since been clonedfrom other plants, and one, CIC-Nt1 (from tobacco), has been demonstrated toform funtional Cl ^- channels, suggesting that at least some of these proteinsdo function as Cl ^- channels in plants [ 7 ].

1. Chloride channels: an emerging molecular picture. Bioessays 19, 117-26
2. Primary structure of Torpedo marmorata chloride channel isolated by expression cloning in Xenopus oocytes. Nature 348, 510-4
3. Transmembrane topology of a CLC chloride channel. Proc. Natl. Acad. Sci. U.S.A. 94, 7633-8
4. Myotonia levior is a chloride channel disorder. Hum. Mol. Genet. 4, 1397-402
5. A common molecular basis for three inherited kidney stone diseases. Nature 379, 445-9
6. A family of putative chloride channels from Arabidopsis and functional complementation of a yeast strain with a CLC gene disruption. J. Biol. Chem. 271, 33632-8
7. Cloning and functional expression of a plant voltage-dependent chloride channel. Plant Cell 8, 701-11