Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters

Electroneutral cation-Cl^– cotransporters compose a family of solute carriers in which cation (Na⁺ or K⁺) movement through the plasma membrane is always accompanied by Cl^– in a 1:1 stoichiometry. Seven well-characterized members include one gene encoding the thiazide-sensitive Na⁺–Cl^– cotransporter, two genes encoding loop diuretic-sensitive Na⁺–K⁺–2Cl^– cotransporters, and four genes encoding K⁺–Cl^– cotransporters. These membrane proteins are involved in several physiological activities including transepithelial ion absorption and secretion, cell volume regulation, and setting intracellular Cl^– concentration below or above its electrochemical potential equilibrium. In addition, members of this family play an important role in cardiovascular and neuronal pharmacology and pathophysiology. Some of these cotransporters serve as targets for loop diuretics and thiazide-type diuretics, which are among the most commonly prescribed drugs in the world, and inactivating mutations of three members of the family cause inherited diseases such as Bartter's, Gitelman's, and Anderman's diseases. Major advances have been made in the past decade as consequences of molecular identification of all members in this family. This work is a comprehensive review of the knowledge that has evolved in this area and includes molecular biology of each gene, functional properties of identified cotransporters, structure-function relationships, and physiological and pathophysiological roles of each cotransporter.