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

Xiao Jian Yuan, Takao Sugiyama, William F. Goldman, Lewis J. Rubin, Mordecai P. Blaustein

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

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-trifluoromethoxyphenylhydrazone (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 fluorescentimaging microscopy techniques were used to measure K+ currents (Ik) and [Ca2-]i, respectively. FCCP (3-5 μM) 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-aminophenoxy)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 (∼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+]; activated Ca2+-activated K+ (Kca) channels. Furthermore, in BAPTA-treated cells, longer application (≥6 min) of FCCP reversibly decreased IK(V) in PA cells bathed in Ca2--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 Ca2+-independent mechanism, presumably the inhibition of oxidative ATP production.

Original languageEnglish (US)
Pages (from-to)C321-C331
JournalAmerican Journal of Physiology - Cell Physiology
Volume270
Issue number1 39-1
DOIs
StatePublished - Jan 1996

Keywords

  • Calcium-activated potassium channel
  • Calcium-activated potassium current
  • Carbonyl cyanide p-trifluoromethoxyphenylhydrazone
  • Mitochondria
  • Voltage-gated potassium channel
  • Voltage-gated potassium current

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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