WNK Protein Kinases Modulate Cellular Cl− Flux by Altering the Phosphorylation State of the Na-K-Cl and K-Cl Cotransporters

Abstract

Precise control of cellular Cl− transport is necessary for many fundamental physiological processes. For example, the intracellular concentration of Cl−, fine-tuned through the coordinated action of cellular Cl− influx and efflux mechanisms, determines whether a neuron’s response to GABA is excitatory or inhibitory. In epithelia, synchrony between apical and basolateral Cl− flux, and transcellular and paracellular Cl− transport, is necessary for efficient transepithelial Cl− reabsorption or secretion. In cells throughout the body, coordination of Cl− entry and exit mechanisms help defend against changes in cell volume. The Na-K-Cl and K-Cl cotransporters of the SLC12 gene family are important molecular determinants of Cl− entry and exit, respectively, in these systems. The WNK serine-threonine kinase family, members of which are mutated in an inherited form of human hypertension, are components of a signaling pathway that coordinates Cl− influx and efflux through SLC12 cotransporters to dynamically regulate intracellular Cl− activity.