Nitric Oxide Signaling Pathway

Nitric oxide (NO), an inorganic gas, acts as a potent second messenger in most animal and plant tissues. NO diffuses out of the cells that produce it and enters the neighboring cells to generate a downstream response. NO synthase (NOS) catalyzes NO production by the deamination of the amino acid arginine. There are three isoforms of NOS. Endothelial cells have endothelial NOS (eNOS), nerve and muscle cells have neuronal NOS (nNOS), and macrophages produce inducible NOS (iNOS) upon exposure to various pathogens.

One of the most crucial roles of NO is relaxing the smooth muscles on the blood vessel walls. NO produced in the endothelial cells has a short half-life of 2-30s and hence can diffuse locally, activating only the neighboring smooth muscle cells. Inside these cells, NO binds guanylyl cyclase and triggers it to convert GTP to cyclic GMP. This leads to an increase in cGMP levels in the cytosol within seconds. cGMP then binds and activates protein kinase G, which disassembles the actin-myosin contractile machinery. This brings about smooth muscle relaxation which causes the blood vessels to dilate and increase blood flow.

NO has been regularly used since the 1860s in the form of the drug nitroglycerine to treat angina. Improper blood flow to the heart muscle leads to severe chest pain or angina. The drug nitroglycerine metabolizes into NO once inside the body. The NO then dilates blood vessels for increased blood flow to the heart, which relieves chest pain.

The quick rise in the cytosolic cGMP due to NO is compensated by its rapid degradation by the cGMP phosphodiesterase (PDE) enzyme, thereby balancing its levels. Some drugs, such as Viagra, work by inhibiting this cGMP phosphodiesterase enzyme. Thus, the cGMP levels stay elevated for a prolonged period, causing relaxation of the smooth muscle of penile blood vessels, thereby increasing the blood flow and erection of the organ.