The mechanism by which the mitochondrial ATP-sensitive K+ channel opening and H2O2 inhibit the mitochondrial permeability transition

Abstract

Myocardial infarction is a manifestation of necrotic cell death as a result of opening of the mitochondrial permeability transition (MPT). Receptor-mediated cardioprotection is triggered by an intracellular signaling pathway that includes phosphatidylinositol 3-kinase, endothelial nitric-oxide synthase, guanylyl cyclase, protein kinase G (PKG), and the mitochondrial K ATP channel (mitoKATP). In this study, we explored the pathway that links mitoKATP with the MPT. We confirmed previous findings that diazoxide and activators of PKG or protein kinase C (PKC) inhibited MPT opening. We extended these results and showed that other K + channel openers as well as the K+ ionophore valinomycin also inhibited MPT opening and that this inhibition required reactive oxygen species. By using isoform-specific peptides, we found that the effects of K ATP channel openers, PKG, or valinomycin were mediated by a PKCε. Activation of PKCε by phorbol 12-myristate 13-acetate or H 2O2 resulted in mitoKATP-independent inhibition of MPT opening, whereas activation of PKCε by PKG or the specific PKCε agonist ψε receptor for activated C kinase caused mitoK ATP-dependent inhibition of MPT opening. Exogenous H 2O2 inhibited MPT, because of its activation of PKCε, with an IC50 of 0.4 (±0.1) μM. On the basis of these results, we propose that two different PKCε pools regulate this signaling pathway, one in association with mitoKATP and the other in association with MPT. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.