Nitric Oxide (NO) is a gaseous material that diffuses freely across cell membranes. It is a free radical (i.e. it has an unpaired electron in the valence shells); that is why it is very reactive and participates in many chemical reactions trying to lose the extra electron(s) to or gain the missing electron(s) from other cell molecules leading to their damage. That explains why Nitric Oxide reacts with many substances inside the body and is consumed quickly at the site of its production.
Nitric Oxide is synthesized within the cells by the enzyme Nitric Oxide Synthase (NOS). The human and mouse genome contains 3 different genes encoding Nitric Oxide Synthases:
1) nNOS (or NOS-1): neuronal NOS found in neurons
2) iNOS (or NOS-2): inducible NOS expressed in astrocytes and microglia of the central nervous system in addition to macrophages and neutrophils.
3) eNOS (or NOS-3): found in the endothelial cells that lining blood vessels. All types of NOS act on arginine with the aid of molecular oxygen and NADPH to produce Nitric Oxide and citrulline.
Whereas the levels of nNOS and eNOS are relatively steady, expression of iNOS genes awaits an appropriate stimulus such as tumor necrosis factor ? and interleukin-1 ?. Both nNOS and eNOS require Ca2+-calmodulin as a cofactor for their activities, iNOS does not. Under normal physiological conditions, nNOS and eNOS produce small quantities of Nitric Oxide. iNOS can produce large and potentially toxic quantities of Nitric Oxide in inflammatory cells recruited to an injury site.
Mechanisms of Nitric Oxide Action:
NO acts as an intercellular and intracellular messenger. The signaling process begins with its binding to protein receptors on or in the cell which initiates an allosteric change (conformational change) in the protein which, in turn, triggers the production of a "second messenger" within the cell. Guanylyl cyclase seems to be the most common protein target for NO which produces the second messenger cyclic guanosine monophosphate (cGMP).
Nitric Oxide is a Vasodilator: the endothelial cells lining the blood vessels release NO that diffuses to the underlying smooth muscle causing its relaxation. That permits the surge of blood to pass through easily at the end of the systole. Knocked-out mice for eNOS suffer from hypertension.
Nitric Oxide and Sepsis: NO is injurious to bacteria and other pathogens. That is why it is produced by macrophages and neutrophils.
Nitric Oxide and the Central Nervous System:
- NO is believed to be produced by tanyctyes of the ependyma.
- NO is an important physiological messenger in the central nervous system such as in the modulation of brain development, synaptic plasticity, cerebral blood flow, sensory processing, and neuroendocrine secretion.- In rats and mice, NO is released by neurons in the CA1 region of the hippocampus and stimulates the NMDA receptors there that are responsible for long-term potentiation (LTP) - a type of memory and learning.
- NO has a dual role in the nervous system. Physiological levels of NO is neuroprotective and neurorestorative, while excess concentrations are neurotoxic.
- Excessive production of NO and its metabolite peroxynitrite (ONOO(-)) is linked to the pathogenesis of some neurodegenerative diseases. This is due to the fact that NO/ONOO(-) causes mitochondrial damage and failure of the respiratory electron transport chain (oxidative phosphorylation) to take place. This leads to neuronal death.
- NO promotes neurogenesis and angiogenesis and enhances neuroblast migration.
- Some NO donors* have been reported to enhance angiogenesis and neurogenesis.
*Nitric Oxide Donors include DETA-NONOate, SNAP, GSNO, and NOC.
References:
- Calabrese V, Mancuso C, Calvani M, Rizzarelli E, Butterfield DA, Stella AM (2007): Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nat Rev Neurosci. 8: 766-75
- Estrada C, Murillo-Carretero M (2005): Nitric oxide and adult neurogenesis in health and disease. Neuroscientist. 11: 294-307.
- Stewart VC, Heales SJ (2003): Nitric oxide-induced mitochondrial dysfunction: implications for neurodegeneration Free Radic Biol Med. 34: 287-303
- Stuart-Smith K (2002): Demystified?Nitric oxide. Mol Pathol. 55: 360-6.
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