RIP3 S-nitrosylation contributes to cerebral ischemic neuronal injury.
Cerebral ischemia-reperfusion is associated with NMDA receptor-mediated calcium influx which activates neuronal nitric oxide synthase (nNOS) and consequently induces NO production. NO S-nitrosylates cellular protein and aggravates neuronal injury. Receptor-interacting protein 3 (RIP3) is a sensor molecule regulating cell apoptosis and necrosis. However, the roles of RIP3 in cerebral ischemic ... injury remain elusive. In this study, we reported that RIP3 could be S-nitrosylated by the exogenous NO donor GSNO in HEK293 cells and the Cys(119) residue was the key nitrosylation site. In addition, we found that cerebral ischemia induced RIP3 S-nitrosylation at different time points of reperfusion, which was coupling with RIP3 phosphorylation (which is associated with its activation) and its interaction with receptor-interacting protein 1 (RIP1), and this process facilitated cerebral ischemic injury. Treatment with NMDA receptor antagonist MK801, or nNOS inhibitor 7NI, diminished RIP3 S-nitrosylation and reduced neuronal damage. Taken together, these data demonstrated that NMDAR-dependent RIP3 S-nitrosylation induced by ischemia facilitated its activation in the early stages of ischemia, blocking this process could reduce the ischemia neuronal injury.
Mesh Terms:
Aldehyde Oxidoreductases, Animals, Apoptosis, Brain Ischemia, Disease Models, Animal, Dizocilpine Maleate, Excitatory Amino Acid Antagonists, Glucose, HEK293 Cells, Humans, Hypoxia, Male, Neurons, Nitric Oxide Synthase Type I, Phosphorylation, Protein-Serine-Threonine Kinases, Rats, Rats, Sprague-Dawley, Signal Transduction, Time Factors
Aldehyde Oxidoreductases, Animals, Apoptosis, Brain Ischemia, Disease Models, Animal, Dizocilpine Maleate, Excitatory Amino Acid Antagonists, Glucose, HEK293 Cells, Humans, Hypoxia, Male, Neurons, Nitric Oxide Synthase Type I, Phosphorylation, Protein-Serine-Threonine Kinases, Rats, Rats, Sprague-Dawley, Signal Transduction, Time Factors
Brain Res.
Date: Nov. 19, 2015
PubMed ID: 26319693
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