Voltage-dependent calcium channel and nitric oxide-cyclic guanosine monophosphate signaling pathway (VDCC/NO-cGMP pathway)

The signaling axis involving voltage-dependent calcium channels (VDCCs) and the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway is a fundamental regulator of intestinal smooth muscle tone and motility. VDCCs, particularly the L-type CaV1.2, are responsible for the calcium influx that triggers muscle contraction (UniProt: P16234). This process is modulated by NO, a key inhibitory neurotransmitter in the gut, which stimulates soluble guanylate cyclase (sGC) to produce cGMP (Sanders & Ward, 2019, Am J Physiol Gastrointest Liver Physiol). The resulting activation of protein kinase G (PKG) leads to the inhibition of VDCCs and the activation of potassium channels, collectively promoting smooth muscle relaxation (Groneberg et al., 2010, Handb Exp Pharmacol). Dysfunctions in this pathway are linked to various gastrointestinal motility disorders, including achalasia, where impaired NO signaling leads to failure of the lower esophageal sphincter to relax. Therapeutic strategies often involve the use of calcium channel blockers to reduce contractility or NO donors and phosphodiesterase inhibitors to enhance the inhibitory signaling arm (PubChem: CID 145068).

Other names

NO-cGMP-VDCC axisNitric oxide-mediated smooth muscle relaxation pathwayNO-sGC-cGMP-PKG-VDCC signalingNitric oxide-cGMP-calcium channel signaling

Nitric oxide activates soluble guanylate cyclase to produce cGMP, which activates protein kinase G to inhibit voltage-dependent calcium channels, leading to decreased intracellular calcium and smooth muscle relaxation.