cGMP-PKG signaling pathway (cGMP-PKG)

The cGMP-PKG signaling pathway is a fundamental intracellular cascade that translates extracellular signals into diverse physiological responses, including vasodilation, platelet inhibition, and cardiac protection (Frontiers in Pharmacology, 2022) [1.2.1]. The pathway is initiated by the production of cyclic guanosine monophosphate (cGMP) by either soluble guanylate cyclase (sGC), activated by nitric oxide, or particulate guanylate cyclase (pGC), activated by natriuretic peptides (MDPI, 2021) [1.3.2]. The primary effector of this pathway is cGMP-dependent protein kinase (PKG), which phosphorylates a variety of substrates to regulate calcium homeostasis and smooth muscle relaxation (NIH, 2020) [1.2.3]. Dysregulation of cGMP-PKG signaling is a hallmark of several pathological conditions, most notably heart failure, pulmonary arterial hypertension, and erectile dysfunction (Frontiers in Pharmacology, 2022) [1.2.1]. In these diseases, the pathway is often impaired due to reduced nitric oxide bioavailability or increased cGMP degradation by phosphodiesterases like PDE5 (NIH, 2020) [1.3.1]. Therapeutic strategies frequently target this pathway to restore cGMP levels, utilizing drugs such as PDE5 inhibitors (e.g., sildenafil), sGC stimulators (e.g., riociguat), and neprilysin inhibitors (e.g., sacubitril) (MDPI, 2021) [1.3.2]. These interventions have proven effective in improving hemodynamics and reducing adverse cardiac remodeling in clinical settings (Frontiers in Pharmacology, 2022) [1.2.1].

Other names

NO-sGC-cGMP-PKG axisNatriuretic peptide-pGC-cGMP-PKG axiscGMP-dependent protein kinase signaling pathwaycGMP signaling cascade

Stimulation of soluble guanylate cyclase (sGC), inhibition of phosphodiesterase 5 (PDE5), inhibition of neprilysin to increase natriuretic peptides, and direct activation of particulate guanylate cyclase (pGC).