Invited Review: cGMP-dependent protein kinase signaling mechanisms in smooth muscle: from the regulation of tone to gene expression

Abstract

cGMP is a second messenger that produces its effects by interacting with intracellular receptor proteins. In smooth muscle cells, one of the major receptors for cGMP is the serine/threonine protein kinase, cGMP-dependent protein kinase (PKG). PKG has been shown to catalyze the phosphorylation of a number of physiologically relevant proteins whose function it is to regulate the contractile activity of the smooth muscle cell. These include proteins that regulate free intracellular calcium levels, the cytoskeleton, and the phosphorylation state of the regulatory light chain of smooth muscle myosin. Other studies have shown that vascular smooth muscle cells (VSMCs) that are cultured in vitro may cease to express PKG and will, coincidentally, acquire a noncontractile, synthetic phenotype. The restoration of PKG expression to the synthetic phenotype VSMC results in the cells acquiring a more contractile phenotype. These more recent studies suggest that PKG controls VSMC gene expression that, in turn, regulates phenotypic modulation of the cells. Therefore, the regulation of PKG gene expression appears to be linked to phenotypic modulation of VSMC. Because several vascular disorders are related to the accumulation of synthetic, fibroproliferative VSMC in the vessel wall, it is likely that changes in the activity of the nitric oxide/cGMP/PKG pathway is involved the development of these diseases.

Acute effects of 17β-estradiol on femoral veins from adult gonadally intact and ovariectomized female pigs

“…NO activates directly K ϩ channels on smooth muscle cells (7). However, release of NO and activation of K ϩ channels may not be independent or mutually exclusive events because NO also relaxes veins by increasing cGMP levels (30), which in turn may activate Ca 2ϩ activated K ϩ channels (31,52). Cyclic nucleotide-gated channels, protein kinases, and/or phosphodiesterases (32) could be additional cGMP targets.…”

Hypoxia enhances a cGMP-independent nitric oxide relaxing mechanism in pulmonary arteries

“…Multiple mechanisms have been identified through which cGMP induces smooth muscle relaxation, where the dominant system mediating relaxation appears to vary between the vascular segments and the experimental conditions. In smooth muscle, relaxation through cGMP is generally associated with multiple processes regulated by activation of cGMPdependent protein kinase that decrease intracellular Ca 2ϩ , the sensitivity of contraction to Ca 2ϩ , and the phosphorylation of myosin light chains (MLC) (17). NO can promote vascular relaxation through hyperpolarization by opening Ca 2ϩ -activated K ϩ channels through cGMP-dependent (1) and cGMP-independent (3) mechanisms.…”

New nitric oxide donors based on ruthenium complexes

“…An increase in cellular cGMP levels occurs in response to the activation of the membrane guanylyl-cyclase or more commonly by activation of soluble guanylyl-cyclase by NO (28). Numerous studies have inferred activation of PKG in response to diverse ligands, presumably downstream of NO production (29). NO has two signaling pathways, a cGMP-dependent one and a cGMP independent one, which could directly activate K + channels (30).…”