The mechanism by which the mitochondrial ATP-sensitive K+ channel opening and H2O2 inhibit the mitochondrial permeability transition.
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 (mitoK(ATP)). In this study, we explored the pathway that links mitoK(ATP) 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 PKCepsilon. Activation of PKCepsilon by phorbol 12-myristate 13-acetate or H(2)O(2) resulted in mitoK(ATP)-independent inhibition of MPT opening, whereas activation of PKCepsilon by PKG or the specific PKCepsilon agonist psiepsilon receptor for activated C kinase caused mitoK(ATP)-dependent inhibition of MPT opening. Exogenous H(2)O(2) inhibited MPT, because of its activation of PKCepsilon, with an IC(50) of 0.4 (+/-0.1) microm. On the basis of these results, we propose that two different PKCepsilon pools regulate this signaling pathway, one in association with mitoK(ATP) and the other in association with MPT.
Costa
Alexandre D T
ADT
Department of Biology, Portland State University, Portland, Oregon 97201-0751.
Jakob
Regina
R
Department of Biology, Portland State University, Portland, Oregon 97201-0751.
Costa
Cinthia L
CL
Department of Biology, Portland State University, Portland, Oregon 97201-0751.
Andrukhiv
Ksenia
K
Department of Biology, Portland State University, Portland, Oregon 97201-0751.
West
Ian C
IC
Department of Biology, Portland State University, Portland, Oregon 97201-0751.
Garlid
Keith D
KD
Department of Biology, Portland State University, Portland, Oregon 97201-0751. Electronic address: garlid@pdx.edu.
D000255:Adenosine Triphosphate / Q000737:chemistry*; D000818:Animals; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010539:Permeability; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015221:Potassium Channels / Q000737:chemistry*; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D014018:Tissue Distribution
D015221:Potassium Channels; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D051744:Protein Kinase C-epsilon