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 a strong affinity for heme proteins such as guanylyl cyclase, but there is evidence that NO may have a regulatory role by oxidizing sulfhydryl groups of non-heme proteins such as those on the NMDA receptor. The half-life of NO is 3-7 seconds, but because of its rapid rate of diffusion it can be expected to influence a sphere of cells in a radius of about 100μm from the site of its generation. One mechanism by which NO is thought to modulate long-term potentiation (LTP) and long-term depression (LTD) by the activation of guanylyl cyclase and the subsequent elevation of cGMP. In fact, elevation of cGMP induced by NMDA is enhanced by L-arginine and inhibited by L-NMMA. It is presumed that NO augments glutamate release, but whether this involves a linkage with cGMP is not known. Centrally, activation of the NMDA receptor is strongly linked with the rapid generation of NO in neurons, but other agonists such as kainate and acetylcholine have been shown to generate NO under selective conditions and regions of the brain. However, there are several lines of evidence suggesting that NO is a neurotoxicant. Stimulation of NMDA receptor results in the release of superoxide anion as well as NO. At least part of NO-induced toxicity results from its reaction with superoxide anion which results in the formation of a strong oxidant, peroxinitrite.