Modulation of mitochondrial ATP-dependent K+ channels by protein kinase C

Toshiaki Sato, Brian O'Rourke, Eduardo Marbán

Research output: Contribution to journalArticle

Abstract

Pharmacological openers of mitochondrial ATP-dependent K+ (mitoK(ATP)) channels mimic ischemic preconditioning, and such cardioprotection can be prevented by mitoK(ATP) channel blockers. It is also known that protein kinase C (PKC) plays a key role in the induction and maintenance of preconditioning. To look for possible mechanistic links between these 2 sets of observations, we measured mitochondrial matrix redox potential as an index of mitoK(ATP) channel activity in rabbit ventricular myocytes. The mitoK(ATP) channel opener diazoxide (100 μmol/L) partially oxidized the matrix redox potential. Exposure to phorbol 12-myristate 13-acetate (PMA, 100 nmol/L) potentiated and accelerated the effect of diazoxide. These effects of PMA were blocked by the mitoK(ATP) channel blocker 5-hydroxydecanoate, which we verified to be a selective blocker of the mitoK(ATP) channel in simultaneous recordings of membrane current and flavoprotein fluorescence. The inactive control compound 4α-phorbol (100 nmol/L) did not alter the effects of diazoxide. We conclude that the activity of mitoK(ATP) channels can be regulated by PKC in intact heart cells. Potentiation of mitoK(ATP) channel opening by PKC provides a direct mechanistic link between the signal transduction of ischemic preconditioning and pharmacological cardioprotection targeted at ATP-dependent K+ channels.

Original languageEnglish (US)
Pages (from-to)110-114
Number of pages5
JournalCirculation research
Volume83
Issue number1
DOIs
StatePublished - Jul 13 1998

Keywords

  • 5- hydroxydecanoate
  • Diazoxide
  • Mitochondria
  • Preconditioning
  • Protein kinase C

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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