MODULATION OF MITOCHONDRIAL ATP-DEPENDENT K-KINASE-C( CHANNELS BY PROTEIN)

Pharmacological openers of mitochondrial ATP-dependent K+ (mitoK(ATP)) channels mimic ischemic preconditioning, and such cardioprotection ca n be prevented by mitoK(ATP) channel blockers. It is also known that p rotein kinase C (PKC) plays a key role in the induction and maintenanc e of preconditioning, To look for possible mechanistic links between t hese 2 sets of observations, we measured mitochondrial matrix redox po tential as an index of mitoK(ATP) channel activity in rabbit ventricul ar myocytes. The mitoK(ATP) channel opener diazoxide (100 mu mol/L) pa rtially oxidized the matrix redox potential. Exposure to phorbol 12-my ristate 13-acetate (PMA, 100 nmol/L) potentiated and accelerated the e ffect of diazoxide. These effects of PMA were blocked by the mitoK(ATP ) channel blocker 5-hydroxydecanoate, which we verified to be a select ive blocker of the mitoK(ATP) channel in simultaneous recordings of me mbrane current and flavoprotein fluorescence. The inactive control com pound 4 alpha-phorbol (100 nmol/L) did not alter the effects of diazox ide, We conclude that the activity of mitoK(ATP) channels can be regul ated by PKC in intact heart cells. Potentiation of mitoK(ATP) channel opening by PKC provides a direct mechanistic link between the signal t ransduction of ischemic preconditioning and pharmacological cardioprot ection targeted at ATP-dependent K+ channels.