Protein kinase G type I in cardiac myocytes: unmasked at last?

Abstract

This editorial refers to ‘Stress-dependent dilated cardiomyopathy in mice with cardiomyocyte-restricted inactivation of cyclic GMP-dependent protein kinase I’[†][1], by S. Frantz et al. , on page 1233 Increasing evidence over the past decade has suggested that elevations in myocardial cGMP may protect against adverse ventricular remodelling. cGMP is produced in different cell types comprising cardiac muscle, including vascular smooth muscle and endothelial cells, fibroblasts, monocytes/macrophages, and cardiac myocytes (CMs) themselves, all of which participate in remodelling. In the latter, cGMP is produced either from particulate guanylate cyclase (pGC) contained within GC-A [natriuretic peptide receptor type A (NPRA) activated by atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)] and GC-B [(NPRB) activated by C-type natriuretic peptide (CNP)], or from soluble GC (sGC) activated by NO and CO. Given the diffusible nature of NO, CM sGC can theoretically be activated by NO from autocrine sources [endogenously expressed nitric oxide synthases (NOS)], paracrine sources (i.e. mainly from endothelial and inflammatory cells), and, possibly, exogenous NO. cGMP-dependent protein kinase type I (cGKI) is part of a family of cGMP-activated protein kinases (PKs) encoded by two different genes; one encoding cGKIα and cGKIβ (through alternative splicing), and the other encoding cGKII, a membrane-bound PK classically detected in the intestinal brush border.1 Together with cGMP-modulated phosphodiesterases (PDEs), cGKs represent the main effectors of cGMP signalling in cardiovascular (and other) tissues. As such they modulate the function of key proteins involved in excitation–contraction (EC) coupling ( Figure 1 ), contractility, cell survival, metabolism, and CM hypertrophic remodelling ( Figure 2 ). Recent studies have highlighted the functional compartmentation of cGMP pools within CM, each susceptible to activate a specific subset of cGK and effectors; this would be in line with the identification of cGK anchoring proteins2 (akin to the PKA-associated A kinase anchoring proteins family) that … [1]: #fn-2