Voltage-Gated Cl^– Channel Family

The voltage-gated Cl^– channel (CLC) family in mammals contains at least nine different genes, encoding the Cl^– channels CLC-Ka (CLC-K1), CLC-Kb (CLC-K2), and CLC-1 to CLC-7. All CLC channels bear the common transmembrane topology, with intracellular N- and C-termini and 10-12 TM domains. The expression pattern of different CLC channels varies from ubiquitous to highly tissue-specific. In excitable cells, CLC channels may be involved in the stabilization of membrane potential. For instance, the mutations in the skeletal muscle-specific CLC-1 channel lead to increased excitability of the muscle. In epithelial cells, CLC channels are involved in Cl^– transport. CLC-Ka (CLC-K1) mediates a transepithelial Cl^– transport in the thin ascending limb of Henle’s loop and is essential for urinary concentrating mechanisms, while CLC-Kb (CLC-K2) is a basolateral Cl^– channel in distal nephron segments and is necessary for Cl^– reabsorption. CLC-2 seems to be involved in Cl^– secretion by intestinal and airway epithelial cells. The kidney-specific CLC-5 is located in the endosomal membrane and seems to provide the Cl^– conductance necessary for intravesicular acidification which is required for the process of endocytosis. The ubiquitously expressed CLC-3 is considered a candidate for volume regulated or swelling-regulated Cl^– current (I_Cl .vol), which is widely present in mammalian cells. The function of other CLC channels is highly unknown.

References

1. Waldegger, S. and Jentsch, T.J. (2000) J. Am. Soc. Nephrol. 11, 1331.
2. Jentsch, T.J. et al. (1999) Pflugers. Arch. 437, 783.
3. Uchida, S. et al. (2000) Am. J. Physiol. 279, F802.