The generation of nitric oxide and its roles in neurotransmission and neurotoxicity

The N-methyl-D-aspartate (NMDA) receptor plays a key role in synaptic plasticity and is thought to underlie memory, learning and development of the nervous system. The NMDA receptor is a ligand-gated ion channel complex that contains distinct recognition sites for endogenous and exogenous ligands, including glutamate, glycine, Mg2+, Zn2+ and noncompetitive blockers such as MK-801. In the central nervous system, nitric oxide (NO) is produced in some neurons following activation of excitatory amino acids receptors, particularly those of the NMDA receptor. Nitric oxide is synthesized from a L-arginine by the cytoplasmic enzyme nitric oxide synthase (NOS) which is a calcium dependent enzyme, and this pathway is inhibited by the analogues of L-arginine such as NG-monomethyl-L-arginine (L-NMMA) and is augmented by NMDA receptor activation. Activation of the NMDA receptor results in the elevation of intracellular calcium ([Ca2+]i) which in turn activates NOS via the calcium-calmodulin complex. Nitric oxide is not a classical neurotransmitter in the central nervous system since it is not released by exocytosis and does not interact with a receptor protein but rather diffuses rapidly across the membrane and binds with the iron in heme-containing proteins. Nitric oxide can serve as both an oxidizing and reducing agent. It has strong affinity for heme proteins such as guanylyl cyclase, but there is evident that NO may have a regulatory role by oxidizing sulfhydryl groups of non-heme proteins such as those on the NMDA receptor.(ABSTRACT TRUNCATED AT 250 WORDS)