Differential sensitivity of inward rectifier K+ channels to metabolic inhibitors

Abstract

Inhibition of inward rectifier K+ channels under ischemic conditions may contribute to electrophysiological consequences of ischemia such as cardiac arrhythmia. Ischemia causes metabolic inhibition, and the use of metabolic inhibitors is one experimental method of simulating ischemia. The effects of metabolic inhibitors on the activity of inward rectifier K+ channels Kir2.1, Kri2.2, and Kri2.3 were studied by heterologous expression in Xenopus oocytes and two-electrode voltage clamp. 10 μM carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) inhibited Kri2.2 and Kri2.3 currents but was without effect on Kir2.1 currents. The rate of decline of current in FCCP was faster for Kir2.3 than for Kri2.2. Kri2.3 was inhibited by 3 mM sodium azide (NAN3), whereas Kri2.1 and Kit2.2 were not. Kri2.2 was inhibited by 10 mM NaN3. All three of these inward rectifiers were inhibited by lowering the pH of the solution perfusing inside-out membrane patches. Kir2.3 was most sensitive to pH (pK = 6.9), whereas Kir2.1 was least sensitive (pK = 5.9). For ir2.2 the pK was 6.2. These results demonstrate the differential sensitivity of these inward rectifiers to metabolic inhibition and internal pH. The electrophysiological response of a particular cell type to ischemia may depend on the relative expression levels of different inward rectifier genes.