Chloride channel

Chloride channels are a superfamily of poorly understood ion channels consisting of approximately 13 members.

Chloride channels display a variety of important physiological and cellular roles that include regulation of pH, volume homeostasis, organic solute transport, cell migration, cell proliferation and differentiation. Based on sequence homology the chloride channels can be subdivided into a number of groups. The importance of one such group, the CLC family of chloride channels, can be seen from the diseases that develop when the channel does not function normally.

This family of ion channels contains 10 or 12 transmembrane helices. Each protein forms a single pore. It has been shown that some members of this family form homodimers. In terms of primary structure, they are unrelated to known cation channels or other types of anion channels. Three ClC subfamilies are found in animals. ClC-1 (UniProt P35523) is involved in setting and restoring the resting membrane potential of skeletal muscle, while other channels play important parts in solute concentration mechanisms in the kidney [3]. These proteins contain two Pfam PF00571 domains.

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Pathology

Bartter's syndrome, which is associated with renal salt wasting and hypokalemic alkalosis, is due to the defective transport of chloride ions and associated ions in the thick ascending loop of Henle. CLC-Kb has been implicated.

Another inherited disease that affects the kidney organs is Dent's Disease, characterised by low molecular weight proteinuria and hypercalciuria where mutations in CLC-5 are implicated.

Thomsen disease is associated with domininate mutations and Becker disease with recessive mutations in CLCN1.

Functions

Chloride channels are important for setting cell resting membrane potential and maintaining proper cell volume. These channels conduct Cl^- as well as other anions such as HCO₃^-, I^-, SCN^-, and NO₃^-. The structure of these channels are not like other known channels. Chloride channel subunits contain between 1 and 12 transmembrane segments. Some members of this family are activated by voltage, while others are activated by Ca²⁺, extracellular ligands, and pH among other modulators.^[1]

Commercial Applications

Chloride channels are disrupted in fleas, causing death, with some organic materials. Selamectin is the active ingredient in Revolution, a topical insecticide and antihelminthic used on dogs and cats. Selamectin works by replacing glutamate which normally interacts with receptors that open chloride channels at muscle synapses found in parasites. Unlike glutamate, selamectin activates the chloride current without desensitization, thereby producing prolonged hyperpolarization and impaired muscle contraction.

Human genes

• CLCN1, CLCN2, CLCN3, CLCN4, CLCN5, CLCN6, CLCN7
• CLCNKA, CLCNKB
• CLIC1, CLIC2, CLIC3, CLIC4, CLIC5, CLIC6
• CLNS1A, CLNS1B
• CLCA1, CLCA2, CLCA3, CLCA4

See also

• Cystic fibrosis transmembrane conductance regulator

References

• 1. ^ Suzuki M., Morita T. and Iwamoto, T. (2006) Diversity of Cl(-) channels. Cell Mol Life Sci. 63(1):12-24. Entrez PubMed 16314923

Further reading

• [1]. Reconstitution of functional voltage-gated chloride channels from complementary fragments of CLC-1. Schmidt-Rose T, Jentsch TJ; J Biol Chem 1997;272:20515-20521. PubMed
• [2]. Mutations in the human skeletal muscle chloride channel gene (CLCN1) associated with dominant and recessive myotonia congenita. Zhang J, George AL Jr, Griggs RC, Fouad GT, Roberts J, Kwiecinski H, Connolly AM, Ptacek LJ; Neurology 1996;47:993-998. PubMed
• [3]. ClC chloride channels. Mindell JA, Maduke M; Genome Biol 2001;2:REVIEWS3003. PubMed