The channels that control K ؉ homeostasis by mediating K ؉ secretion across the apical membrane of renal tubular cells have recently been cloned and designated ROMK1, -2, and -3. Native apical K ؉ channels are indirectly regulated by the K ؉ concentration at the basolateral membrane through a cascade of intracellular second messengers. It is shown here that ROMK1 (K ir 1.1) channels are also directly regulated by the extracellular (apical) K ؉ concentration, and that this K ؉ regulation is coupled to intracellular pH. The K ؉ regulation and its coupling to pH were assigned to different structural parts of the channel protein. K ؉ regulation is determined by the core region, which comprises the two hydrophobic segments M1 and M2 and the P region. Decoupling from pH was achieved by exchanging the N terminus of ROMK1 by that of the pH-insensitive channel IRK1 (K ir 2.1). These results suggest an allosteric regulation of ROMK1 channels by extracellular K ؉ and intracellular pH, which may represent a novel link between K ؉ homeostasis and pH control.

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