cGMP and mitochondrial K+ channels - Compartmentalized but closely connected in cardioprotection.

The 3',5'-cyclic guanosine monophosphate (cGMP) pathway triggers cytoprotective responses and improves cardiomyocyte survival during myocardial ischemia and reperfusion (I/R) injury. These beneficial effects were attributed to NO-sensitive guanylyl cyclase (GC) induced cGMP production leading to activation of cGMP-dependent protein kinase I (cGKI). Cyclic GKI in turn causes phosphorylation of multiple substrates, which eventually facilitates opening of mitochondrial ATP-sensitive potassium channels (mitoKATP ) and Ca2+ -activated potassium channels of the BK type (mitoBK). Accordingly, agents activating mitoKATP or mitoBK provide protection against I/R-induced damages. Here we give an up-to-date summary of the infarct-limiting actions exhibited by the GC/cGMP axis and discuss how mitoKATP and mitoBK, which are present at the inner mitochondrial membrane, confer mito- and cytoprotective effects on cardiomyocytes exposed to I/R injury. In view of this, we believe that the functional connection between the cGMP cascade and mitoK+ channels should be exploited further as adjunct to reperfusion therapy in myocardial infarction.