ATP consumption by uncoupled mitochondria activates sarcolemmal KATP channels in cardiac myocytes

Norihito Sasaki, Toshiaki Sato, Eduardo Marban, Brian O'Rourke

Research output: Contribution to journalArticle

Abstract

We tested whether close coupling exists between mitochondria and sarcolemma by monitoring whole cell ATP-sensitive K+ (KATP) current (IK,ATP) as an index of subsarcolemmal energy state during mitochondrial perturbation. In rabbit ventricular myocytes, either pinacidil or the mitochondrial uncoupler dinitrophenol (DNP), which rapidly switches mitochondria from net ATP synthesis to net ATP hydrolysis, had little immediate effect on IK,ATP. In contrast, in the presence of pinacidil, exposure to 100 μM DNP rapidly activated IK,ATP with complex kinetics consisting of a quick rise [time constant of IK,ATP increase (τ) = 0.13 ± 0.01 min], an early partial recovery (τ = 0.43 ± 0.04 min), and then a more gradual increase. This DNP-induced activation of IK,ATP was reversible and accompanied by mitochondrial flavoprotein oxidation. The F1Fo-ATPase inhibitor oligomycin abolished the DNP-induced activation of IK,ATP. The initial rapid rise in IK,ATP was blunted by atractyloside (an adenine nucleotide translocator inhibitor), leaving only a slow increase (τ = 0.66 ± 0.17 min, P < 0.01). 2,4-Dinitrofluorobenzene (a creatine kinase inhibitor) slowed both the rapid rise (τ = 0.20 ± 0.01 min, P < 0.05) and the subsequent declining phase (τ = 0.88 ± 0.19 min, P ≤ 0.05). From single KATP channel recordings, we excluded a direct effect of DNP on KATP channels. Taken together, these resuits indicate that rapid changes in F1Fo-ATPase function dramatically alter subsarcolemmal energy charge, as reported by pinacidil-primed KATP channel activity, revealing cross-talk between mitochondria and sarcolemma. The effects of mitochondrial ATP hydrolysis on sarcolemmal KATP channels can be rationalized by reversal of F1Fo-ATPase and the facilitation of coupling by the creatine kinase system.

Original languageEnglish (US)
Pages (from-to)H1882-H1888
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume280
Issue number4 49-4
DOIs
StatePublished - Apr 2001

Keywords

  • ATP hydrolysis
  • ATP-sensitive K channels
  • Dinitrophenol
  • Patch-clamp

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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