Long-lasting inhibition of presynaptic metabolism and neurotransmitter release by protein S-nitrosylation

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 111 presynaptic nerve endings We examined the effects of exogenous sources of RNS on the vesicular and nonvesicular L-[H-3]glutamate release from rat brain synaptosomes NO/RNS donors, such as spermine NONOate, MAHMA NONOate, S-nitroso-L-cysteine. and SIN-I, 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 >1 h 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 mitochondria] 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 (C) 2010 Elsevier Inc All rights reserved