Src-family protein tyrosine kinase phosphorylates WNK4 and modulates its inhibitory effect on KCNJ1 (ROMK)

Genetic, biochemical, and animal model studies have implicated with-no-lysine kinase 4 (WNK4) in regulation of the balance between renal salt reabsorption and K secretion. It has been proposed that serum/glucocorticoid-induced kinase 1 (SGK1)-induced phosphorylation of WNK4 plays an important role in switching from inhibiting KCNJ1 (ROMK) channels during volume depletion to promoting K secretion during increasing K intake. However, it is not understood why a high SGK1 level fails to stimulate ROMK channels during the volume depletion, whereas it increases ROMK channel activity and K secretion during high K intake. The present study provides insights into the mechanism illustrating how SFK-induced phosphorylation of WNK4 regulates ROMK to distinguish the physiologic response to hyperkalemia and volume depletion.