cGMP-dependent protein kinase 1 (PRKG1) (PRKG1)

cGMP-dependent protein kinase 1 (PRKG1), also known as PKG1, is a serine/threonine kinase that serves as a central mediator of the nitric oxide (NO) and natriuretic peptide signaling pathways in the heart (UniProt P14619). In cardiomyocytes, PRKG1 regulates cardiac contractility and relaxation by phosphorylating key proteins such as phospholamban, troponin I, and L-type calcium channels (PubMed: 22465037). It acts as a critical brake against pathological cardiac hypertrophy and fibrosis by inhibiting pro-growth signaling pathways like the calcineurin-NFAT axis (PubMed: 30139473). Reduced PRKG1 activity is implicated in the development of heart failure, particularly heart failure with preserved ejection fraction (HFpEF), and hypertensive heart disease (NCBI Gene ID 5592). While direct pharmacological activators of PRKG1 are mostly used in experimental settings, the enzyme is effectively targeted indirectly by drugs that increase cGMP levels, such as PDE5 inhibitors (e.g., sildenafil) and soluble guanylate cyclase stimulators (e.g., vericiguat) (StatPearls: Nitroglycerin). Enhancing PRKG1 activity is a therapeutic strategy aimed at improving myocardial relaxation and preventing adverse remodeling in various cardiovascular pathologies.

Other names

Protein kinase G 1PKG1cGKIcGK1PRKG1Cyclic GMP-dependent protein kinase I

The primary mechanism of action for drugs modulating this target is the elevation of intracellular cyclic guanosine monophosphate (cGMP) levels, which allosterically activates PRKG1. This is achieved through the inhibition of phosphodiesterase 5 (PDE5) or the stimulation/activation of soluble guanylate cyclase (sGC). Once activated, PRKG1 phosphorylates downstream effectors to improve myocardial relaxation and inhibit hypertrophic signaling (PubMed: 22465037).