Targeting nitric oxide to its targets.

Nitric oxide (NO) is now recognized as a major messenger molecule in the nervous system. In specific neuronal pathways, NO functions alternatively as a neurotransmitter and as a second messenger. Neuronal-type nitric oxide synthase is a widely distributed (nNOS or Type I) calmodulin-regulated enzyme and is coupled to a variety of neurotransmitter systems in brain and peripheral tissues. NO formation is linked in cerebellum to NMDA receptor activity, in myenteric neurons to neuronal nicotinic receptor activity, and in skeletal muscle to sarcolemmal depolarization. Coupling of nNOS activity to alternative calcium sources appears to be mediated, in part, by tethering nNOS to specific membrane proteins. In skeletal muscle, nNOS physically associates with the sarcolemmal dystrophin complex through a GLGF protein-association motif present near the N terminus of nNOS. This GLGF motif is likely also involved in anchoring nNOS to synaptic membrane complexes in brain. Subcellular targeting of nNOS represents a crucial mechanism for regulation of NO actions in the nervous system.