Circulation Research. 2005;97:329-336
Published online before print July 21, 2005,
doi: 10.1161/01.RES.0000178451.08719.5b
(Circulation Research. 2005;97:329.)
© 2005 American Heart Association, Inc.
Protein Kinase G Transmits the Cardioprotective Signal From Cytosol to Mitochondria
Alexandre D.T. Costa,
Keith D. Garlid,
Ian C. West,
Thomas M. Lincoln,
James M. Downey,
Michael V. Cohen,
Stuart D. Critz
From the Department of Biology (A.D.T., K.D.G., I.C.W.), Portland State University, Portland, Ore; and the Departments of Physiology (T.M.L., J.M.D., M.V.C.), Medicine (M.V.C.), and Cell Biology and Neuroscience (S.D.C.), University of South Alabama, Mobile.
Correspondence to Stuart D. Critz, PhD, Department of Cell Biology and Neuroscience, MSB 2342, University of South Alabama, College of Medicine, Mobile, AL 36688. E-mail scritz{at}usouthal.edu
Ischemic and pharmacological preconditioning can be triggered by an intracellular signaling pathway in which Gi-coupled surface receptors activate a cascade including phosphatidylinositol 3-kinase, endothelial nitric oxide synthase, guanylyl cyclase, and protein kinase G (PKG). Activated PKG opens mitochondrial KATP channels (mitoKATP) which increase production of reactive oxygen species. Steps between PKG and mitoKATP opening are unknown. We describe effects of adding purified PKG and cGMP on K+ transport in isolated mitochondria. Light scattering and respiration measurements indicate PKG induces opening of mitoKATP similar to KATP channel openers like diazoxide and cromakalim in heart, liver, and brain mitochondria. This effect was blocked by mitoKATP inhibitors 5-hydroxydecanoate, tetraphenylphosphonium, and glibenclamide, PKG-selective inhibitor KT5823, and protein kinase C (PKC) inhibitors chelerythrine, Ro318220, and PKC-
peptide antagonist V1-2. MitoKATP are opened by the PKC activator 12-phorbol 13-myristate acetate. We conclude PKG is the terminal cytosolic component of the trigger pathway; it transmits the cardioprotective signal from cytosol to inner mitochondrial membrane by a pathway that includes PKC-.
Key Words: ATP-sensitive K+ channel • cGMP • preconditioning • protein kinase C • protein kinase G
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