Nitric oxide: A pleiotropic signal in the nervous system

AD= : Alzheimer disease; cAMP= : cyclic adenosine monophosphate; cGMP= : cyclic guanosine monophosphate; CREB= : cyclic adenosine monophosphate response element-binding protein; DRG= : dorsal root ganglion; Drp-1= : dynamin-related protein 1; EET= : epoxyeicosatrienoic acid; eNOS= : endothelial nitric oxide synthase; FAD= : flavin adenine dinucleotide; FMN= : flavin mononucleotide; GABA= : γ-aminobutyric acid; GADPH= : glyceraldehyde-3-phophate dehydrogenase; HETE= : hydroxyeicosatetraenoic acid; Hsp= : heat shock protein; iNOS= : inducible nitric oxide synthase; MELAS= : mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes; MS= : multiple sclerosis; mtNOS= : mitochondrial variant of NOS; NADPH= : nicotinamide-adenine dinucleotide phosphate; NF-kB= : nuclear factor κB; NMDAR= : NMDA receptor; nNOS= : neuronal nitric oxide synthase; NO= : nitric oxide; NOS= : nitric oxide synthase; PD= : Parkinson disease; PKG= : protein kinase G; PNS= : peripheral nervous system; RNS= : reactive nitrogen species; SAH= : subarachnoid hemorrhage; SNO= : S-nitrosothiol; sGC= : soluble (cytosolic) guanylyl cyclase; VIP= : vasoactive intestinal polypeptide Nitric oxide (NO) is a gaseous chemical transmitter that is produced from the amino acid l-arginine by the members of the NO synthase (NOS) family of proteins. NO is involved in several important functions in the CNS and peripheral nervous system (PNS), including modulation of neurotransmission and regulation of local blood flow and immune responses. NO interacts with intracellular targets to trigger several signal transduction pathways. In the CNS, NO participates in synaptic modulation and plasticity, control of sleep, body temperature, and neurosecretion. In the PNS, NO mediates vasodilation and relaxation of the visceral smooth muscle. However, when produced in excess and in the setting of oxidative stress, NO becomes toxic, leading to formation of reactive nitrogen species (RNS), which cause cellular damage. These neurotoxic effects of NO derivatives may be involved in the pathogenesis of cerebral ischemia, inflammation, neoplasia, and neurodegenerative disorders. There are several comprehensive reviews on the physiologic and pathophysiologic roles of NO in the nervous system.1,–,12 ### Catalytic activity. The NOS family of enzymes catalyzes the oxidation of l-arginine to form l-citrulline and NO (figure 1). NOS is a dimeric enzyme; each monomer is composed of 2 distinct catalytic domains, an amino (NH2)-terminal oxygenase domain and a carboxy (COOH)-terminal reductase domain. The oxygenase domain is the binding site for heme, oxygen (O2), tetrahydrobiopterin (BH4), and l-arginine; the reductase domain binds flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), and reduced nicotinamide-adenine dinucleotide phosphate (NADPH). The catalytic mechanism involves flavin-mediated electron transport from NADPH to the heme center, where O2 is reduced and incorporated into the guanidine nitrogen of l-arginine, producing NO and l-citrulline. Figure 1 General features of nitric oxide signaling Nitric oxide (NO*) is produced from arginine by action of NO synthase (NOS) in the presence of heme, oxygen (O2), tetrahydrobiopterin (BH4) as flavin adenine dinucleotide (FAD), flavin mononucleotide …