Modulation of mitochondrial ATP-dependent K+ channels by protein kinase C.
Pharmacological openers of mitochondrial ATP-dependent K+ (mitoKATP) channels mimic ischemic preconditioning, and such cardioprotection can be prevented by mitoKATP 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 mitoKATP channel activity in rabbit ventricular myocytes. The mitoKATP channel opener diazoxide (100 micromol/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 mitoKATP channel blocker 5-hydroxydecanoate, which we verified to be a selective blocker of the mitoKATP channel in simultaneous recordings of membrane current and flavoprotein fluorescence. The inactive control compound 4alpha-phorbol (100 nmol/L) did not alter the effects of diazoxide. We conclude that the activity of mitoKATP channels can be regulated by PKC in intact heart cells. Potentiation of mitoKATP 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.
Department of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
T
T
Sato
B
B
O'Rourke
E
E
Marbán
D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D003652:Decanoic Acids / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D006880:Hydroxy Acids / Q000494:pharmacology; D008929:Mitochondria, Heart / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology*; D011493:Protein Kinase C / Q000494:pharmacology*; D011817:Rabbits
D003652:Decanoic Acids; D006880:Hydroxy Acids; D015221:Potassium Channels; C052853:5-hydroxydecanoic acid; D000255:Adenosine Triphosphate; D011493:Protein Kinase C; D003981:Diazoxide