Neuronal nitric oxide synthase and downstream nitric oxide–cyclic guanosine monophosphate–protein kinase G motility pathway (nNOS/NO/cGMP/PKG pathway)

The neuronal nitric oxide synthase (nNOS) and downstream nitric oxide–cyclic guanosine monophosphate–protein kinase G (NO–cGMP–PKG) pathway is a fundamental signaling cascade responsible for mediating inhibitory neurotransmission and smooth muscle relaxation (PubMed: 1981545). In the gastrointestinal tract, nNOS (encoded by the NOS1 gene) located in the myenteric plexus produces NO, which acts as a gaseous neurotransmitter that diffuses into smooth muscle cells to activate soluble guanylyl cyclase (sGC) (UniProt: P29475). This activation results in the production of cGMP, which in turn activates PKG, leading to the phosphorylation of proteins that sequester calcium or open potassium channels, ultimately causing muscle relaxation (PubMed: 10617687). This pathway is critical for normal peristalsis and the relaxation of sphincters, such as the lower esophageal sphincter and the pylorus. Defects in this pathway, particularly the loss of nNOS-expressing neurons, are strongly associated with motility disorders like achalasia and gastroparesis (PubMed: 21238734). Therapeutic strategies often focus on augmenting this pathway using PDE5 inhibitors like Sildenafil to prevent cGMP degradation or sGC stimulators like Riociguat to enhance cGMP production, thereby restoring motility or vascular tone (PubMed: 15184705, PubMed: 23883907).

Other names

NOS1 signaling pathwayNitrergic signaling pathwaynNOS-mediated smooth muscle relaxation pathwayNO-cGMP-PKG signaling cascade

The pathway is initiated by Neuronal Nitric Oxide Synthase (nNOS) producing Nitric Oxide (NO), which activates soluble guanylyl cyclase (sGC) to increase cyclic guanosine monophosphate (cGMP) levels. Elevated cGMP activates Protein Kinase G (PKG), which phosphorylates various targets (e.g., VASP, phospholamban) to decrease intracellular calcium and induce smooth muscle relaxation (PubMed: 10617687).