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 nNOS Signaling at Neuronal Synapses

Nitric oxide (NO) is a gaseous low reactivity free radical with the ability to freely cross cell membranes. In neural tissues it is a mediator of synaptic signaling, regulator of synaptic architecture and neural plasticity, promoter of neurotoxicity and a wide array of other effects that are cell type and context specific. NO can modulate the release of neurotransmitters such as acetylcholine, catecholamines, excitatory and inhibitory amino acids, serotonin, histamine and adenosine. NO-dependent release of neurotransmitters is generally linked to a guanylyl cyclase-coupled NO receptors (NO_GCR)) which catalyzes cGMP formation and activation of cGMP-dependent protein kinase (PKG). NO is involved in synaptic plasticity phenomena such as long-term potentiation (LTP) and depression (LTD), and synaptogenesis. Supraphysiological NO levels induced by hyperexcitatory stimulation of N-methyl-D aspartate (NMDA) receptors by glutamate mediate neurotoxicity (excitotoxicity).

Nitric oxide (NO) production in neural cells is coupled to the stimulation of N-methyl-D-aspartate (NMDA) receptors by glutamate through calcium activation of nitric oxide synthase (NOS). Nitric oxide synthases (EC 1.14.13.39) are calmodulin binding enzymes that convert L-arginine and oxygen into citrulline and NO. Neural nitric oxide synthase (nNOS, NOS-1, NOS-I, NOS type I) isoform alpha (nNOSα, nNOSalpha) contains a PDZ domain that facilitates its binding to NMDA receptors through postsynaptic density protein 95 (PSD95). Tethering of nNOSalpha to NMDAR regulated calcium channels facilitates its activation by glutamate induced calcium flow into the cell. Under normal glutamate excitatory conditions, the flow of calcium is controlled and NO mediates intended signaling effects. Pathological conditions often lead to over-stimulation of the NMDA receptors by glutamate followed by elevation of NO to levels that induce neurotoxicity (excitotoxicity). Excitotoxicity is implicated in many neurodegenerative conditions including ischemia, traumatic brain injury, Parkinson's disease, Huntingdon's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS).