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

Abstract

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 Kir2 subfamily expressed in Xenopus oocytes, using two-electrode voltage-clamp, patch-clamp, and intracellular pH recording. FCCP inhibited Kir2.2 and Kir2.3 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 Kir2.2 and Kir2.3 currents by FCCP. The pH dependence of Kir2.2 was shifted to higher pH in membrane patches from FCCP-treated oocytes compared to control oocytes. Therefore, the inhibition of Kir2.2 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 Kir2.1 homomeric channels were insensitive to FCCP, both Kir2.1-Kir2.2 and Kir2.1-Kir2.3 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.

• Authors: Anthony Collins, Maureen Larson
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 202 Issue 1 Pg. 76-86 (Jan 2005) ISSN: 0021-9541 [Print] United States
• PMID: 15389543 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 2005 Wiley-Liss, Inc.

Chemical References

• Enzyme Inhibitors
• Imidazoles
• Kcnj4 protein, mouse
• Potassium Channels
• Potassium Channels, Inwardly Rectifying
• Uncoupling Agents
• inward rectifier potassium channel 2
• Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
• imidazole

Topics

• Animals
• Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone (pharmacology)
• Cell Membrane (drug effects, metabolism)
• Dimerization
• Energy Metabolism (drug effects, physiology)
• Enzyme Inhibitors (pharmacology)
• Female
• Heart Failure (metabolism, physiopathology)
• Hydrogen-Ion Concentration (drug effects)
• Imidazoles (pharmacology)
• Intracellular Fluid (drug effects, metabolism)
• Ischemia (metabolism, physiopathology)
• Membrane Potentials (drug effects, physiology)
• Mitochondria (drug effects, metabolism)
• Oocytes
• Patch-Clamp Techniques
• Potassium Channels (drug effects, genetics, metabolism)
• Potassium Channels, Inwardly Rectifying (drug effects, genetics, metabolism)
• Uncoupling Agents (pharmacology)
• Xenopus laevis