The renal inward rectifier potassium channel Kir7.1 has been proposed to be functionally important for tubular K(+) recycling and secretion. This study investigated the regulation of Kir7.1 by PKA and PKC. Cloned human Kir7.1 channels were expressed heterologously in Xenopus oocytes. After pharmacological PKC activation, Kir7.1 currents were strongly inhibited. Co-application of PKC inhibitors attenuated this effect. Inactivation of PKC consensus sites also strongly attenuated the effect with a single site ((201)S) being essential for almost the total PKC sensitivity. In contrast, PKA activation induced an increase of Kir7.1 currents. This effect was absent in mutant Kir7.1 channels lacking PKA consensus site (287)S. In summary, this study demonstrates the dual regulation of Kir7.1 channel function by PKA and PKC. Structurally, these regulations depend on two key residues in the C-terminal channel domain ((Ser)201 for PKC and (Ser)287 for PKA).