Nitric oxide (NO) is formed endogenously by a family of enzymes known as NO synthases (NOS).Three distinct isoforms of NOS have been identified: nNOS, iNOS and eNOS. Glutamate is the most effective activator of NO biosynthesis in most brain regions. NO is generated via a five-electron oxidation of a terminal guanidine nitrogen on L-Arginine by nNOS. The reaction yields L-Citrulline in addition to NO. Free cytosolic Ca2+ stimulates nNOS through interaction with CALM and Calcineurin. In the CNS, NO synthesis is regulated by the influx of Ca2+ through receptor-dependent channels, in particular following post-synaptic stimulation of NMDAR by glutamate. Elevated cytosolic Ca2+ concentrations are required for CALM binding to nNOS, which then activates the enzyme. NO release is also regulated by PKC in resting neurons.NO actions in brain and muscle depend crucially upon the association of nNOS with specific protein complexes. In the brain, the 160kDa nNOSα is the predominant splice variant and contains an N-terminal PDZ domain. The PDZ domain of nNOS binds to a similar PDZ domain from the post-synaptic protein PSD95, which in turn binds to the cytosolic tail of NMDAR. These molecular interactions explain how Ca2+ influx through NMDARs is efficiently coupled to NO synthesis and activity. This membrane-localized nNOS complex is further linked to cytoplasmic signal transduction pathways via the physical interaction of nNOS with DexRas1 and the adapter protein CAPON, which activates a downstream MAPK pathway. CAPON competes with nNOS for PDZ domains, binding to the enzyme and forcing it to disassociate itself from the plasma membrane. Furthermore, CAPON anchors nNOS to other macromolecules such as DexRas1.
NO is a unique messenger molecule involved in the regulation of diverse physiological processes including smooth muscle contractility, platelet reactivity, central and peripheral neurotransmission and the cytotoxic actions of immune cells. At the cellular level, NO signaling is essential for two forms of neuronal plasticity: Long term potentiation in the hippocampus and long term depression in the cerebellum.