cGMPSignale

cGMPSignale, or cGMP signaling, refers to intracellular signaling pathways driven by cyclic guanosine monophosphate (cGMP). cGMP levels rise when guanylate cyclases are activated: soluble guanylate cyclase (sGC) by nitric oxide (NO) and membrane-bound guanylate cyclases by natriuretic peptides such as ANP and BNP. The increased cGMP acts on effectors including protein kinase G (PKG), cyclic nucleotide-gated (CNG) ion channels, and other cGMP-binding proteins to elicit cellular responses.

cGMP production and breakdown: NO released from endothelial or neuronal sources activates sGC to produce cGMP. Natriuretic peptides bind to their receptor guanylate cyclases on target cells, also increasing cGMP synthesis. cGMP is degraded by phosphodiesterases (PDEs); PDE5 is highly selective for cGMP, PDE6 is prevalent in retinal photoreceptors, and PDE1/9 have broader activity. The balance between synthesis and hydrolysis controls signal strength and duration.

Targets and physiological effects: PKG activation leads to phosphorylation of diverse substrates, resulting in reduced Ca2+ sensitivity and relaxation of smooth muscle, decreased platelet aggregation, and modulation of ion channels. In the retina, cGMP-gated channels regulate phototransduction; in other tissues, cGMP influences vascular tone and neuronal signaling. cGMP signaling intersects with cAMP pathways and can modulate various cellular processes through localized signaling domains.

Clinical relevance: NO–cGMP signaling is central to vascular regulation and penile erection. PDE5 inhibitors (e.g., sildenafil, tadalafil) enhance cGMP signaling and are used to treat erectile dysfunction and pulmonary arterial hypertension. Therapies aiming to increase sGC activity or decrease cGMP breakdown are explored in cardiovascular and retinal diseases. Regulation of cGMP signaling is influenced by oxidative stress, NO availability, and compartmentalization within cells.