Molecular physiology of renal ClC chloride channels/transporters

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Abstract
Recent findings relevant to the renal ClC chloride channels/transporters are reviewed with a focus on structure-function relationships, regulation of trafficking, role in blood pressure control, and pharmacology. The ClC proteins include plasma membrane Cl channels and vesicular Cl/H exchangers. Recent experiments have revealed further details regarding the structure and mechanism of the permeation path. X-ray crystallographic and electrophysiological studies have identified two glutamate residues required for gated Cl movement and proton permeation in bacterial and two mammalian (ClC-4, ClC-5) ClC transporters. In renal ClC channels (ClC-Ka, ClC-Kb), both glutamate residues are replaced by valine, leading to speculation about critical differences between transporter and channel members of the ClC family. New information about the physiological regulation of renal ClC proteins has implicated the Nedd4 ubiquitin ligases and serum and glucocorticoid-inducible kinases in controlling functional levels of ClC-5 and ClC-K/barttin in renal cells. ClC proteins are critical for many clinically relevant physiological events. New insights into fundamental structure-function relationships, mechanisms of ion translocation, cellular regulation, and roles in human disease have increased attention on ClC proteins as important potential therapeutic targets.