ABSTRACT
The close interrelationship between the diatomic radical nitric oxide (NO) and the Af-methyl-D-aspartate (NMDA) subtype of glutamate receptors in the central nervous system (CNS) has been an area of intensive research over the last decade. In 1988, Garthwaite, Bredt, and co-workers demonstrated that NMDA receptor stimulation was coupled with NO-mediated activation of soluble guanylate cy clase (GC) (6,19,20). NADPH-diaphorase reactivity, used for decades to visualize subpopulations of neurons histologically, was found to be associated with the isozyme of nitric oxide synthase (NOS) [termed neuronal nitric oxide synthase (nNOS)] that catalyzes the formation of NO from arginine (7,30). Subsequently, two other isozymes of NOS were described, i.e., endothelial (ecNOS) and induc ible (iNOS), which also utilize NADPH as a cofactor (25,46,50). The activity of both ecNOS and nNOS are closely regulated by the concentration of cytosolic
calcium, acting through a binding site for calmodulin. In some neurons, nNOS can associate with the R1 subunit of membrane-bound NMD A receptors via an interaction of their respective PDZ motifs with the docking protein PSD-95 (8,60). In this manner, the influx of calcium ions gated through an NMDA receptor-nNOS complex can result in the formation of NO, temporally and spatially linking NO with glutamate release. In addition to effects mediated through GC, NO can modulate neurotransmitter release, neuronal development, synaptic plas ticity, and gene expression.
