Nitric oxide–cyclic GMP signaling pathway (NO–cGMP pathway)

The **nitric oxide–cyclic GMP (NO–cGMP) pathway** is a central **signal transduction cascade** in mammalian physiology that mediates a range of cellular responses including smooth muscle relaxation, inhibition of platelet aggregation, neurotransmission, and cellular growth regulation[1][2][6][7]. In this pathway, nitric oxide (NO), synthesized by nitric oxide synthases (NOS), freely diffuses into neighboring cells and binds to the heme group of **soluble guanylyl cyclase (sGC)**[5][2][8]. This interaction stimulates sGC to convert guanosine triphosphate (GTP) into **cyclic guanosine monophosphate (cGMP)**, a second messenger[2][4][5][8]. cGMP mediates downstream effects by activating **cGMP-dependent protein kinase (PKG)**, **cyclic nucleotide-gated channels**, and regulating **phosphodiesterases (PDEs)**, which degrade cGMP[1][2][4][6]. Malfunction of this pathway is implicated in cardiovascular diseases, neurodegeneration, and other major conditions[1][2][7]. Pharmacologic targeting of its components (e.g., with NO donors, PDE inhibitors like sildenafil, and sGC activators) underpins therapies for diseases such as pulmonary hypertension and heart failure[1][4][6]. **Note:** - The pathway itself is **not a single molecule or receptor**, but a multi-component signaling system. - Distinct, druggable targets in the pathway include enzymes like sGC and PDE5, not the entire pathway. - Listing the pathway as a "therapeutic target" is imprecise; instead, specify the **individual proteins** (e.g., sGC, PDE5) within the pathway. - If a canonical entry is required for structured data, use the major effector:**soluble guanylyl cyclase (sGC)**.

Other names

Nitric oxide–cyclic guanosine monophosphate pathwayNO–cGMP pathwayNO–sGC–cGMP pathway

NO donors increase NO to act on soluble guanylyl cyclase (sGC); sGC stimulators/activators directly activate/restore sGC function; Phosphodiesterase inhibitors block cGMP degradation