Protein Kinase G (PKG) Inhibitors
cGMP produces its effects by interacting with intracellular receptor proteins. A primary action of elevated cGMP levels is the stimulation of cGMP-dependent protein kinase (PKG), which catalyzes the phosphorylation of a number of physiologically relevant proteins involved in contractile activity of smooth muscle cells. The mammalian PKG family consists of PKGIa and Ib, splice forms derived from one gene, and PKGII, encoded by a second gene. They are ubiquitous effector enzymes that regulate a variety of physiological processes in response to nitric oxide and natriuretic agonists. Cells of the cardiovascular system, such as fibroblasts and certain types of endothelial cells, contain PKGI. Smooth muscle cells are rich in PKGIa and Ib, platelets and T lymphocytes contain PKGIb, and cardiac myocytes contain PKGIa. It is important to note that PKGs are lost in many primary cell types upon passaging in cell culture and may not be detected in many cell lines. Studies have shown that cultured vascular smooth muscle cells (VSMCs) may stop expressing PKG and acquire a non-contractile phenotype. The restoration of PKG expression can result in the cells acquiring a more contractile phenotype. This is an important observation because several vascular disorders result from accumulation of noncontractile VSMC in the vessel wall. In endothelial cells PKGI phosphorylates and activates eNOS, which reduces its Ca2+-dependence. Also, in endothelial cells, PKGI and PKGII are known to phosphorylate 6-pyruvoyltetrahydropterin synthase to produce tetrahydrobiopterin, a required cofactor for eNOS activation. More recently PKG has also been linked to brown fat cell differentiation and mitochondrial biogenesis.
References:
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