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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 (ICl .vol), which is widely present in mammalian cells. The function of other CLC channels is highly unknown.


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