AJP - Cell Physiology, Vol 270, Issue 1 C321-C331, Copyright © 1996 by American Physiological Society

ARTICLES

A mitochondrial uncoupler increases KCa currents but decreases KV currents in pulmonary artery myocytes

X. J. Yuan, T. Sugiyama, W. F. Goldman, L. J. Rubin and M. P. Blaustein
Department of Medicine, University of Maryland School of Medicine, Baltimore, USA.

Intracellular free Ca2+ concentration ([Ca2+]i) and ATP play important roles in the regulation of K- channels in pulmonary artery (PA) myocytes. Previous studies have demonstrated that hypoxia and the metabolic inhibitor, 2-deoxy-D-glucose, decrease voltage-gated K+ (KV) currents [IK(V)] and thereby depolarize PA myocytes; these effects lead to a rise in [Ca2+]i. Here, we used carbonyl cyanide p-trifluoromethoxyphenyl-hydrazone (FCCP), a protonophore that uncouples mitochondrial respiration from ATP production, to test whether the inhibition of oxidative phosphorylation affects K+ channel activities in rat PA myocytes. Patch-clamp and fluorescent-imaging microscopy techniques were used to measure K+ currents (IK) and [Ca2+]i, respectively. FCCP (3-5 microM) reversibly raised [Ca2-]i in the presence and absence of external Ca2+. This effect was prevented by pretreating the cells with the membrane-permeable Ca2+ chelator, 1,2-bis(2-amino-phenoxy) ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA-AM). This suggests that much of the FCCP-evoked rise in [Ca2-]i was due to Ca2+ release from intracellular stores. Brief exposure to FCCP (approximately 2 min) reversibly enhanced Ik. This augmentation was not influenced by glibenclamide, an ATP-sensitive K channel blocker, but was eliminated by pretreatment with BAPTA-AM. This implies that the FCCP-evoked rise in [Ca2+]i activated Ca(2+)-activated K- (Kca) channels. Furthermore, in BAPTA-treated cells, longer application (> or = 6 min) of FCCP reversibly decreased IK(V) in PA cells bathed in Ca(2+)-free solution. These results demonstrate that FCCP affects KCa and Kv channels by different mechanisms. FCCP increases IK[Ca] by raising [Ca2+]i primarily as a result of Ca2+ release, but decreases IK(V) by a Ca(2+)-independent mechanism, presumably the inhibition of oxidative ATP production.

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