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
Brain Res.
Date: Nov. 19, 2015
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