Nitric oxide–soluble guanylyl cyclase–cyclic guanosine monophosphate signaling pathway (NO–sGC–cGMP pathway)

The nitric oxide–cyclic GMP signaling pathway is a fundamental biological cascade involved in regulating vascular tone, neurotransmission, immune responses, cell proliferation/apoptosis, and smooth muscle relaxation. It begins with the enzymatic synthesis of nitric oxide by nitric oxide synthases from L‐arginine. As a gaseous second messenger molecule, NO diffuses into adjacent cells where it binds its primary receptor—soluble guanylyl cyclase—activating it to convert GTP into cyclic GMP. Elevated cGMP then activates protein kinase G and other effectors leading to physiological outcomes such as vasodilation. Dysregulation at any step can contribute to cardiovascular diseases like hypertension or heart failure; conversely sustained overproduction may cause tissue toxicity seen in sepsis or chronic inflammation. Multiple drugs—including nitrates for angina and PDE5 inhibitors for erectile dysfunction—exploit different nodes within this cascade for therapeutic benefit.

Other names

Nitric oxide signaling pathwayNO/cGMP signalingNO-sGC-cGMP axisNitric oxide signal transduction

Drugs act by one or more of the following mechanisms: - Donating/exogenously supplying nitric oxide to activate sGC directly. - Stimulating soluble guanylyl cyclase to increase cGMP production. - Inhibiting phosphodiesterases that degrade cGMP to prolong its action. These actions lead to increased cGMP levels in target tissues resulting in vasodilation or other downstream effects