title: S-nitrosylation of c-Src via NMDAR-nNOS module promotes c-Src activation and NR2A phosphorylation in cerebral ischemia/reperfusion.
abstract: Previous studies suggested that activated c-Src promote the tyrosine phosphorylation of NMDA receptor subunit NR2A, and thus aggravate the injury induced by transient cerebral ischemia/reperfusion (I/R) in rat hippocampus CA1 region. In this study, we examined the effect of nitric oxide (NO) on the activation of c-Src and the tyrosine phosphorylation of NMDA receptor NR2A subunit. The results show that S-nitrosylation and the phosphorylation of c-Src were induced after cerebral I/R in rats, and administration of nNOS inhibitor 7-NI, nNOS antisense oligonucleotides and exogenous NO donor sodium nitroprusside diminished the increased S-nitrosylation and phosphorylation of c-Src during cerebral I/R. The cysteine residues of c-Src modified by S-nitrosylation are Cys489, Cys498, and Cys500. On the other hand, NMDAR antagonist MK-801 could attenuate the S-nitrosylation and activation of c-Src. Taken together, the S-nitrosylation of c-Src is provoked by NO derived from endogenous nNOS, which is activated by Ca(2+) influx from NMDA receptors, and promotes the auto-phosphorylation at tyrosines and further phosphorylates NR2A. The molecular mechanism we outlined here is a novel postsynaptic NMDAR-nNOS/c-Src-mediated signaling amplification, the 'NMDAR-nNOS → NO → SNO-c-Src → p-c-Src → NMDAR-nNOS' cycle, which presents the possibility as a potential therapeutic target for stroke treatment.
authors.affiliation: Research Center of Biochemistry and Molecular Biology and Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, 84 West Huai-hai Road, Xuzhou 221002, Jiangsu, People's Republic of China.
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Tang
authors.forename: Chong
authors.initials: C
authors.lastname: Li
authors.forename: Shu-Qun
authors.initials: SQ
authors.lastname: Hu
authors.forename: Yong-Ping
authors.initials: YP
authors.lastname: Wu
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Zong
authors.forename: Chang-Cheng
authors.initials: CC
authors.lastname: Sun
authors.forename: Fa
authors.initials: F
authors.lastname: Zhang
authors.forename: Guang-Yi
authors.initials: GY
authors.lastname: Zhang
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D017209:Apoptosis; D002545:Brain Ischemia / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D003545:Cysteine / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004789:Enzyme Activation; D057809:HEK293 Cells; D006624:Hippocampus / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015427:Reperfusion Injury / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D026422:S-Nitrosoglutathione / Q000494:pharmacology; D019061:src-Family Kinases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D003545:Cysteine; D016291:Dizocilpine Maleate; D007191:Indazoles; D018696:Neuroprotective Agents; D020030:Nitric Oxide Donors; D052248:Nitric Oxide Synthase Type I; D009599:Nitroprusside; D016194:Receptors, N-Methyl-D-Aspartate; D026422:S-Nitrosoglutathione; D019061:src-Family Kinases; C080122:7-nitroindazole