title: Long-lasting inhibition of presynaptic metabolism and neurotransmitter release by protein S-nitrosylation.
abstract: Nitric oxide (NO) and related reactive nitrogen species (RNS) play a major role in the pathophysiology of stroke and other neurodegenerative diseases. One of the poorly understood consequences of stroke is a long-lasting inhibition of synaptic transmission. In this study, we tested the hypothesis that RNS can produce long-term inhibition of neurotransmitter release via S-nitrosylation of proteins in presynaptic nerve endings. We examined the effects of exogenous sources of RNS on the vesicular and nonvesicular L-[(3)H]glutamate release from rat brain synaptosomes. NO/RNS donors, such as spermine NONOate, MAHMA NONOate, S-nitroso-L-cysteine, and SIN-1, inhibited only the vesicular component of glutamate release with an order of potency that closely matched levels of protein S-nitrosylation. Inhibition of glutamate release persisted for >1h after RNS donor decomposition and washout and strongly correlated with decreases in the intrasynaptosomal ATP levels. Post-NO treatment of synaptosomes with thiol-reducing reagents decreased the total content of S-nitrosylated proteins but had little effect on glutamate release and ATP levels. In contrast, post-NO application of the end-product of glycolysis, pyruvate, partially rescued neurotransmitter release and ATP production. These data suggest that RNS suppress presynaptic metabolism and neurotransmitter release via poorly reversible modifications of glycolytic and mitochondrial enzymes, one of which was identified as glyceraldehyde-3-phosphate dehydrogenase. A similar mechanism may contribute to the long-term suppression of neuronal communication during nitrosative stress in vivo.
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Alena
authors.initials: A
authors.lastname: Rudkouskaya
authors.forename: Vasiliy
authors.initials: V
authors.lastname: Sim
authors.forename: Aabha A
authors.initials: AA
authors.lastname: Shah
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Feustel
authors.forename: David
authors.initials: D
authors.lastname: Jourd'heuil
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Mongin
mesh_terms: D000818:Animals; D003545:Cysteine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D024602:Glyceraldehyde-3-Phosphate Dehydrogenase (NADP+)(Phosphorylating) / Q000378:metabolism; D008297:Male; D018377:Neurotransmitter Agents / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D019289:Pyruvic Acid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D026403:S-Nitrosothiols / Q000378:metabolism* / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects; D013997:Time Factors
chemical_list: D018377:Neurotransmitter Agents; D026403:S-Nitrosothiols; D019289:Pyruvic Acid; C021315:S-nitrosocysteine; D024602:Glyceraldehyde-3-Phosphate Dehydrogenase (NADP+)(Phosphorylating); D003545:Cysteine; D004229:Dithiothreitol