The heteromeric inwardly rectifying Kir4.1/Kir5.1 K(+) channel underlies the 
basolateral K(+) conductance in the distal nephron and is extremely sensitive to 
inhibition by intracellular pH. The functional importance of Kir4.1/Kir5.1 in 
renal ion transport has recently been highlighted by mutations in the human 
Kir4.1 gene (KCNJ10) that result in seizures, sensorineural deafness, ataxia, 
mental retardation, and electrolyte imbalance (SeSAME)/epilepsy, ataxia, 
sensorineural deafness, and renal tubulopathy (EAST) syndrome, a complex 
disorder that includes salt wasting and hypokalemic alkalosis. Here, we 
investigated the role of the Kir5.1 subunit in mice with a targeted disruption 
of the Kir5.1 gene (Kcnj16). The Kir5.1(-/-) mice displayed hypokalemic, 
hyperchloremic metabolic acidosis with hypercalciuria. The short-term responses 
to hydrochlorothiazide, an inhibitor of ion transport in the distal convoluted 
tubule (DCT), were also exaggerated, indicating excessive renal Na(+) absorption 
in this segment. Furthermore, chronic treatment with hydrochlorothiazide 
normalized urinary excretion of Na(+) and Ca(2+), and abolished acidosis in 
Kir5.1(-/-) mice. Finally, in contrast to WT mice, electrophysiological 
recording of K(+) channels in the DCT basolateral membrane of Kir5.1(-/-) mice 
revealed that, even though Kir5.1 is absent, there is an increased K(+) 
conductance caused by the decreased pH sensitivity of the remaining homomeric 
Kir4.1 channels. In conclusion, disruption of Kcnj16 induces a severe renal 
phenotype that, apart from hypokalemia, is the opposite of the phenotype seen in 
SeSAME/EAST syndrome. These results highlight the important role that Kir5.1 
plays as a pH-sensitive regulator of salt transport in the DCT, and the 
implication of these results for the correct genetic diagnosis of renal 
tubulopathies is discussed.