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

Abstract

The 3',5'-cGMP pathway triggers cytoprotective responses and improves cardiomyocyte survival during myocardial ischaemia and reperfusion (I/R) injury. These beneficial effects were attributed to NO-sensitive GC induced cGMP production leading to activation of cGMP-dependent protein kinase I (cGKI). cGKI in turn phosphorylates many substrates, which eventually facilitate opening of mitochondrial ATP-sensitive potassium channels (mitoK_ATP ) and Ca²⁺ -activated potassium channels of the BK type (mitoBK). Accordingly, agents activating mitoK_ATP or mitoBK provide protection against I/R-induced damages. Here, we provide an up-to-date summary of the infarct-limiting actions exhibited by the GC/cGMP axis and discuss how mitoK_ATP 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. LINKED ARTICLES: This article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc.

Keywords: 3',5'-cyclic guanosine monophosphate (cGMP); C-type natriuretic peptide (CNP); NO synthase (NOS); NO-sensitive (soluble) guanylyl cyclase (GC or NO-GC); atrial natriuretic peptide (ANP); brain (or B-type) natriuretic peptide (BNP); cGMP-dependent protein kinase I (cGKI); mitochondrial ATP-sensitive potassium (K+) channel (mitoKATP); mitochondrial calcium (Ca2+)-activated K+ channels of the BK type (mitoBK); neutral endopeptidase (NEP); nitric oxide (NO); phosphodiesterase (PDE).