WNK protein kinases modulate cellular Cl- flux by altering the phosphorylation state of the Na-K-Cl and K-Cl cotransporters

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.