Sile Saba, Vanoye Carlos G, George Alfred L
Department of Medicine, Division of Genetic Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0275, USA.
Curr Opin Nephrol Hypertens. 2006 Sep;15(5):511-6. doi: 10.1097/01.mnh.0000242177.36953.be.
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.
对与肾脏ClC氯通道/转运体相关的最新研究成果进行综述，重点关注结构-功能关系、转运调控、在血压控制中的作用以及药理学。
ClC蛋白包括质膜氯通道和囊泡氯/氢交换体。近期实验揭示了有关渗透途径结构和机制的更多细节。X射线晶体学和电生理学研究已确定细菌及两种哺乳动物（ClC-4、ClC-5）ClC转运体中门控性氯移动和质子渗透所需的两个谷氨酸残基。在肾脏ClC通道（ClC-Ka、ClC-Kb）中，这两个谷氨酸残基均被缬氨酸取代，这引发了对ClC家族转运体和通道成员之间关键差异的推测。关于肾脏ClC蛋白生理调控的新信息表明，Nedd4泛素连接酶以及血清和糖皮质激素诱导激酶参与控制肾脏细胞中ClC-5和ClC-K/巴丁蛋白的功能水平。
ClC蛋白对许多临床相关生理事件至关重要。对基本结构-功能关系、离子转运机制、细胞调控以及在人类疾病中的作用的新认识，使人们更加关注ClC蛋白作为重要潜在治疗靶点的地位。
