Signaling neuronal nitric oxide synthase

Grb-2 facilitates the transduction of an extracellular stimulus to an intracellular signaling pathway, (b) The adaptor protein PSD-95 associates through one of its three PDZ domains with the N-methyl-D-aspartic acid (NMDA) receptor. Another PDZ domain associates with a PDZ domain from neuronal nitric oxide synthase (nNOS). Through its interaction with PSD-95, nNOS is localized to the NMDA receptor. Stimulation by glutamate induces an influx of calcium, which activates nNOS, resulting in the production of nitric oxide. 

Raines, K.W., Cao, Gi., Lee, E.K., Rosen, G.M., and Shapiro, R (2006). Neuronal nitric oxide synthase-induced S-nitrosylation of H-Ras inhibits calcium ionophore-mediated extracellular-signal-regulated kinase activity. Biochem. J. 397(2), 329-336. 

The CNS contains a substantial amount of nitric oxide synthase (NOS), which is found within certain classes of neurons. This neuronal NOS is an enzyme activated by calcium-calmodulin, and activation of NMDA receptors, which increases intracellular calcium, results in the generation of nitric oxide. Although a physiologic role for nitric oxide has been clearly established for vascular smooth muscle, its role in synaptic transmission and synaptic plasticity remains controversial. Perhaps the strongest case for a role of nitric oxide in neuronal signaling in the CNS is for long-term depression of synaptic transmission in the cerebellum. 

The gaseous free radical nitric oxide (NO), a non-conventional neural messenger, is synthesized in neurons by the enzyme nitric oxide synthase (NOS), which can be revealed in histological sections by NADPH-diaphorase histochemistry or NOS immunohisto-chemistry. The role of NO in neural signaling has raised considerable interest (see, for example, Schmidt and Walter, 1994), stemming also from the finding that NOS has a discrete distribution in subsets of brain neurons, including intense expression in neuronal subsets of the striatum (Vincent, 2000). 

---