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J. Biol. Chem., Vol. 277, Issue 39, 35815-35818, September 27, 2002

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Differential Sensitivity of Inward Rectifier K⁺ Channels to Metabolic Inhibitors^*

Anthony Collins and Maureen Larson

From the Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon 97331-3507

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 K_ir2.1, K_ir2.2, and K_ir2.3 were studied by heterologous expression in Xenopus oocytes and two-electrode voltage clamp. 10 µM carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) inhibited K_ir2.2 and K_ir2.3 currents but was without effect on K_ir2.1 currents. The rate of decline of current in FCCP was faster for K_ir2.3 than for K_ir2.2. K_ir2.3 was inhibited by 3 mM sodium azide (NaN₃), whereas K_ir2.1 and K_ir2.2 were not. K_ir2.2 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. K_ir2.3 was most sensitive to pH (pK = 6.9), whereas K_ir2.1 was least sensitive (pK = 5.9). For K_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.

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