Nitric Oxide Function in Humans
Why is nitric oxide (NO) so important?
To start, NO has unique properties for a signalling molecule: it is small, and rapidly permeates cell membranes and aqueous solutions. It is also highly reactive, chemically modifying (nitrosylating) the amino acid cysteine, found in most proteins. As it is so reactive, it gets depleted easily and its range is relatively short. Because of its potential to interact with almost every protein, we are only beginning to understand the manifold effects of the NO/NOx signaling in cells and the human body. For example, in the brain, NO modifies ion channels, such as glutamate receptors, and reversibly changes their properties. NMDA receptors, which play a crucial role in synaptic plasticity and memory formation, are significantly inhibited by NO.
NO signaling has been comparatively well studied in the regulation of blood flow, which earned its discoverers a Nobel Prize in 1998. Soluble guanyl cyclase (sGC) is a cytoplasmic enzyme in smooth muscle cells found in blood vessel walls. It acts as a receptor of NO coming from surrounding tissues, and coordinates it with a specialized heme cofactor. Upon activation by locally available NO, it produces cyclic GMP, an important secondary messenger, that further activates protein kinase G (PKG), which phosphorylates many targets, including troponin I, an important protein in smooth muscle contraction. This relaxes the muscle, opening up the lumen of the blood vessel, improving the blood flow. Nitroglycerin, which has been used to treat chest pain due to heart ischemia since 1878, works by being converted to nitric oxide, dilating the blood vessels, decreasing heart workload and improving heart oxygenation. Erectile disfunction drugs such as Viagra and Cialis exert their effect through the same pathway. They block cGMP degradation, extending the action of locally produced NO and thus increasing inflow of blood into the tissue in question.
Finally, the NO/NOx signalling system is very important in regulating inflammation. Low concentrations of NO down-regulate inflammation by inhibiting cell adhesion, cytokine and chemokine production and leukocyte adhesion and migration. NO-releasing non-steroidal anti inflammatory drugs (NO-NSAIDs) are new therapeutic agents. Also, when inflamed, human tissue can sometimes produce large quantities of NO, combined with superoxide.
NO can come from many sources, adding yet another layer of complexity. There are three isoforms of NO synthase, which oxidizes the guanidine moiety of the amino acid arginine, releasing NO. Each of those isoforms (endothelial, neuronal and inducible) have distinct functions. Another enzyme, xanthine oxidoreductase can produce NO from nitrite. Protein disulfide isomerase makes NO from S-nitrosothiols, in addition to other sources, some yet undiscovered. AOBiome believes that an important source of NO are Nitrosomonas, commensal bacteria historically colonized human skin.