Cardiovascular Research Advance Access [Accepted Manuscript] published online on October 25, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm050
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cGMP Signaling in Pre- and Postconditioning: The Role of Mitochondria
1 Department of Biology, Portland State University, Portland, OR 97201
2 Department of Physiology, Pharmacology, Metabolism and Cardiovascular Diseases, University of Toledo College of Medicine, Toledo, OH 43614
3 Departments of Physiology, University of South Alabama College of Medicine, Mobile, Alabama 36688
4 Departments of Medicine, University of South Alabama College of Medicine, Mobile, Alabama 36688
* Corresponding author: Dr. Keith D. Garlid Dept of Biology Portland State University Portland, OR 97201 phone (503) 725 8967 fax (503) 725 3888 garlid{at}pdx.edu
Much of cell death from ischemia/reperfusion in heart and other tissues is generally thought to arise from mitochondrial permeability transition (MPT) in the first minutes of reperfusion. In ischemic preconditioning, agonist binding to Gi protein-coupled receptors prior to ischemia triggers a signaling cascade that protects the heart from MPT. We believe the cytosolic component of this trigger pathway terminates in activation of guanylyl cyclase resulting in increased production of cGMP and subsequent activation of protein kinase G (PKG). PKG phosphorylates a protein on the mitochondrial outer membrane (MOM), which then causes the mitochondrial KATP channel (mitoKATP) on the mitochondrial inner membrane to open, leading to increased production of reactive oxygen species (ROS) by the mitochondria. This implies that the protective signal is somehow transmitted from the MOM to its inner membrane. This is accomplished by a series of intermembrane signaling steps that includes PKC? activation. The resulting ROS then activate a second PKC pool which, through another signal transduction pathway termed the mediator pathway, causes inhibition of MPT and reduction in cell death.
KEYWORDS mitochondrial KATP channel; mitochondrial permeability transition; protein kinase C; protein kinase G; reperfusion injury
Time for primary review: 16 days
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