Physiological nitric oxide signaling network (NO signaling)

The physiological nitric oxide (NO) signaling network is a fundamental paracrine system that regulates vascular homeostasis, neurotransmission, and immune function (StatPearls, 2023). NO is synthesized from L-arginine by three distinct nitric oxide synthase (NOS) enzymes: neuronal (nNOS), inducible (iNOS), and endothelial (eNOS) (PubMed, 2021). Once produced, NO diffuses into target cells where it binds to its primary receptor, soluble guanylate cyclase (sGC), triggering the production of the second messenger cyclic guanosine monophosphate (cGMP) (Nature Reviews Cardiology, 2019). This increase in cGMP activates protein kinase G (PKG), leading to physiological effects such as smooth muscle relaxation and inhibition of platelet aggregation (NIH, 2022). Dysregulation of this signaling network is a major contributor to the pathogenesis of hypertension, erectile dysfunction, and pulmonary arterial hypertension (Journal of Clinical Investigation, 2018). Pharmacological agents target various nodes of this network, including NO donors (e.g., nitroglycerin), sGC stimulators (e.g., riociguat), and phosphodiesterase-5 (PDE5) inhibitors (e.g., sildenafil) which prevent cGMP breakdown (Circulation, 2020).

Other names

Nitric oxide-cGMP pathwayNO/sGC/cGMP signaling cascadeEndothelium-derived relaxing factor (EDRF) signaling

Modulation of the network occurs through nitric oxide donation, stimulation of soluble guanylate cyclase, or inhibition of phosphodiesterase-5 to increase intracellular cGMP levels (StatPearls, 2023; Circulation, 2020).