Nitric oxide-responsive signaling pathways (NO signaling pathway)

Nitric oxide-responsive signaling pathways are critical physiological cascades centered on the gasotransmitter nitric oxide (NO). The primary canonical pathway involves NO binding to its intracellular receptor, soluble guanylate cyclase (sGC), which catalyzes the conversion of GTP to the second messenger cyclic guanosine monophosphate (cGMP) (StatPearls, 2023). cGMP then activates downstream effectors such as protein kinase G (PKG) and modulates ion channels and phosphodiesterases to regulate vascular tone, platelet activity, and neurotransmission (Nature Reviews Drug Discovery, 2011). Beyond the cGMP-dependent pathway, NO also signals through non-canonical mechanisms, most notably the S-nitrosylation of specific cysteine residues on target proteins, which can alter enzyme activity and protein-protein interactions (PubMed, 2018). Dysregulation of these pathways is a key driver in cardiovascular diseases, including hypertension and heart failure, as well as in inflammatory and neurodegenerative conditions (Circulation Research, 2003). Pharmacological interventions target these pathways through various mechanisms, including NO donors like nitroglycerin, sGC stimulators like riociguat, and PDE5 inhibitors like sildenafil, all of which aim to enhance or restore NO-mediated signaling for therapeutic benefit (Journal of Clinical Investigation, 2013).

Other names

NO-sGC-cGMP pathwayNitric oxide signalingcGMP signaling pathwayNitric oxide-guanylate cyclase-cGMP pathway

Drugs targeting these pathways act by either donating nitric oxide (NO donors), directly stimulating or sensitizing soluble guanylate cyclase (sGC stimulators/activators), or inhibiting the degradation of the second messenger cGMP (PDE5 inhibitors).