Regulation of inward rectifier K + channels by shift of intracellular pH dependence

The mechanistic link between mitochondrial metabolism and inward rectifier K + channel activity was investigated by studying the effects of a mitochondrial inhibitor, carbonyl cyanide p‐trifluoromethoxyphenylhydrazone (FCCP) on inward rectifiers of the K ir 2 subfamily expressed in Xenopus oocytes, using two‐electrode voltage‐clamp, patch‐clamp, and intracellular pH recording. FCCP inhibited K ir 2.2 and K ir 2.3 currents and decreased intracellular pH, but the pH change was too small to account for the inhibitory effect by itself. However, pre‐incubation of oocytes with imidazole prevented both the pH decrease and the inhibition of K ir 2.2 and K ir 2.3 currents by FCCP. The pH dependence of K ir 2.2 was shifted to higher pH in membrane patches from FCCP‐treated oocytes compared to control oocytes. Therefore, the inhibition of K ir 2.2 by FCCP may involve a combination of intracellular acidification and a shift in the intracellular pH dependence of these channels. To investigate the sensitivity of heteromeric channels to FCCP, we studied its effect on currents expressed by heteromeric tandem dimer constructs. While K ir 2.1 homomeric channels were insensitive to FCCP, both K ir 2.1‐K ir 2.2 and K ir 2.1‐K ir 2.3 heterotetrameric channels were inhibited. These data support the notion that mitochondrial dysfunction causes inhibition of heteromeric inward rectifier K + channels. The reduction of inward rectifier K + channel activity observed in heart failure and ischemia may result from the mitochondrial dysfunction that occurs in these conditions. © 2005 Wiley‐Liss, Inc.