cGMPdependent

cGMP-dependent describes cellular processes, enzymes, or signaling pathways whose activity is regulated by cyclic guanosine monophosphate (cGMP). In animal cells the best-characterized cGMP-dependent effectors are the cGMP-dependent protein kinases (PKG), a family of serine/threonine kinases activated when cGMP binds to their regulatory domains. PKG enzymes relieve autoinhibition of the catalytic domain upon ligand binding and then phosphorylate diverse substrates to elicit physiological responses.

Two main mammalian PKGs exist: PKG I and PKG II, encoded by PRKG1 and PRKG2. PKG I has two tissue- and development-specific isoforms (Iα and Iβ) and is abundant in smooth muscle and platelets; PKG II is found in several tissues including the intestine and brain and is associated with membrane or cytosolic localization. Activation of PKG commonly promotes smooth muscle relaxation, inhibits platelet aggregation, and modulates cardiac calcium handling, among other effects. Downstream targets include myosin light-chain phosphatase regulatory subunit MYPT1, phospholamban, calcium channels, and various ion transporters, often leading to decreased intracellular calcium and altered contractility.

Beyond PKG, other cGMP-dependent mechanisms exist, including cyclic nucleotide-gated (CNG) ion channels in sensory neurons and photoreceptors, which open or close in response to cGMP, translating the second messenger signal into ion flux. cGMP levels are controlled by guanylyl cyclases (membrane-bound and soluble) and by phosphodiesterases that hydrolyze cGMP; NO signaling through soluble guanylyl cyclase is a major source of cGMP in many tissues. Pharmacological manipulation of cGMP signaling underpins therapies for cardiovascular disease and erectile dysfunction.