(NO) One of the highly reactive and readily diffusable FREE RADICALS, found in many tissues in the body. Nitric oxide may act either locally at its site of synthesis, or at adjacent cells, where it binds to a wide variety of cellular components such as ENZYMES, ION CHANNELS and RECEPTORS, thereby altering their function.
In the brain, nitric oxide is synthesized upon demand by NITRIC OXIDE SYNTHASE (NOS), the activity of which is highly regulated by a requirement for CALMODULIN. Increases in intracellular calcium concentrations allow calmodulin to bind to NOS, causing conversion of ARGININE to CITRULLINE, with a concomitant release of nitric oxide. NOS also requires the presence of cofactors including nicotinamide adenine dinucleotide phosphate (NADPH), flavine mononucleotide, flavine adenine dinucleotide, and tetrahydrobiopterin, and an iron-containing HEME element, which act as an electron transport chain in the synthesis of nitric oxide. Several isoforms of NOS have been isolated, of which neuronal NOS and endothelial NOS (named after the tissues from which they were first isolated) are found throughout the brain, co-localized with several transmitter systems. NOS is found in high concentrations in HIPPOCAMPUS, CEREBRAL CORTEX, OLFACTORY BULB, STRIATUM, CEREBELLUM, and several structures in the BRAINSTEM. It is co-localized with CHOLINE ACETYLTRANSFERASE in the PEDUNCULOPONTINE TEGMENTAL NUCLEUS and LATERODORSAL TEGMENTAL NUCLEUS, and with SOMATOSTATIN and NEUROPEPTIDE Y in cortical neurons. NOS is also found in cells of many blood vessels throughout the body, including the CEREBRAL VASCULATURE, and mediates SMOOTH MUSCLE relaxation, leading to increased blood flow.
In many cells, nitric oxide mediates its effect through binding with the heme element of guanylyl cyclase, resulting in increased production of CYCLIC GMP, one of the SECOND MESSENGERS which activates cyclic GMP-dependent PROTEIN KINASE. Protein kinases catalyse the phosphorylation of many cellular enzymes, altering their rate of activity, and may induce such effects as increased transmitter release and altered ion channel permeability. In the hippocampus, nitric oxide release is associated with the stimulation of NMDA RECEPTORS, and has been shown to augment LONG-TERM POTENTIATION (LTP), possibly by acting trans-synaptically to increase transmitter release, suggesting a role in LEARNING and MEMORY. Similarly, nitric oxide has also been implicated in activity-dependent modification of synapses in some areas of the central nervous system during development, by augmenting and preserving synchronously firing neuronal inputs on target neurons or tissues.
Some tissues in the body use the toxic free-radical properties of nitric oxide to alter irreversibly the function of cellular components in order to destroy them. MACROPHAGE cells in the IMMUNE SYSTEM contain an isoform of nitric oxide synthase known as INDUCIBLE NOS. This is used to produce large amounts of nitric oxide which destroys foreign matter phagocytosed by the macrophage cells. Similarly, nitric oxide may be toxic to neurons, if it is produced in large quantities. In ISCHAEMIA and some disease processes, alterations in intracellular calcium concentrations may lead to synthesis of excess nitric oxide which would result in dysfunction, and possibly death of the neuron.
