cGMP signalling in pre- and post-conditioning: the role of mitochondria.
Much of cell death from ischaemia/reperfusion in heart and other tissues is generally thought to arise from mitochondrial permeability transition (MPT) in the first minutes of reperfusion. In ischaemic pre-conditioning, agonist binding to G(i) protein-coupled receptors prior to ischaemia triggers a signalling cascade that protects the heart from MPT. We believe that 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 K(ATP) channel (mitoK(ATP)) 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 signalling steps that includes protein kinase C (PKCepsilon) 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.
Costa
Alexandre D T
AD
Department of Biology, Portland State University, PO Box 751, Portland, OR 97201, USA.
Pierre
Sandrine V
SV
Cohen
Michael V
MV
Downey
James M
JM
Garlid
Keith D
KD
D000818:Animals; D006152:Cyclic GMP / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019157:Ischemic Preconditioning, Myocardial; D008929:Mitochondria, Heart / Q000502:physiology*; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D015221:Potassium Channels / Q000502:physiology; D051744:Protein Kinase C-epsilon / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D015221:Potassium Channels; D017382:Reactive Oxygen Species; C117780:mitochondrial K(ATP) channel; D000071679:Glycogen Synthase Kinase 3 beta; D051744:Protein Kinase C-epsilon; D038362:Glycogen Synthase Kinase 3; D006152:Cyclic GMP