K-Cl Cotransport: Properties and Molecular Mechanism

K-Cl cotransport (COT), defined first in red blood cells as the Cl-dependent, ouabain-insensitive bidirectional K transport, encoded by at least four KCC (kalium-chloride-cotransport) genes, is now recognized as a functional and structural reality in all cell membranes. As functional system, K-Cl COT is necessary for volume and ionic homeostasis. Since its original discovery by swelling red cells in hyposmotic solutions and by treatment with N-ethylmaleimide (NEM), K-Cl COT has been recognized as one of the prime electroneutral, low ion affinity pathways effecting regulatory volume decrease (RVD). This review first summarizes the general properties of K-Cl COT, including ion dependence, kinetics, thermodynamics and regulation in erythrocytes of various species, and then focuses on the newest findings of the molecular mechanisms behind K-Cl COT, the KCC isoforms and their expression in epithelial cells and in Xenopus oocytes. Based on early biophysical studies on red cells amalgamated with the recent molecular expression studies of the four KCC isoforms, K-Cl COT emerges as one of the oldest membrane transporters that is controlled by a complex redox-dependent cascade of kinases and phosphatases, yet to be defined at the molecular level. Whereas RVD is a primeval role of K-Cl COT for survival of cells challenged by hyposmotic environments, maintenance of intracellular Cl ([Cl] I ) levels away from electrochemical equilibrium and K buffering capability during neuronal function are new additions to the list of physiological functions of this system.