title: Protease activated receptor 1 (PAR1) enhances Src-mediated tyrosine phosphorylation of NMDA receptor in intracerebral hemorrhage (ICH).
abstract: It has been demonstrated that Src could modulate NMDA receptor, and PAR1 could also affect NMDAR signaling. However, whether PAR1 could regulate NMDAR through Src under ICH has not yet been investigated. In this study, we demonstrated the role of Src-PSD95-GluN2A signaling cascades in rat ICH model and in vitro thrombin challenged model. Using the PAR1 agonist SFLLR, antagonist RLLFS and Src inhibitor PP2, electrophysiological analysis showed that PAR1 regulated NMDA-induced whole-cell currents (INMDA) though Src in primary cultured neurons. Both in vivo and in vitro results showed the elevated phosphorylation of tyrosine in Src and GluN2A and enhanced interaction of the Src-PSD95-GluN2A under model conditions. Treatment with the PAR1 antagonist RLLFS, AS-PSD95 (Antisense oligonucleotide against PSD95) and Src inhibitor PP2 inhibited the interaction among Src-PSD95-GluN2A, and p-Src, p-GluN2A. Co-application of SFLLR and AS-PSD95, PP2, or MK801 (NMDAR inhibitor) abolished the effect of SF. In conclusion, our results demonstrated that activated thrombin receptor PAR1 induced Src activation, enhanced the interaction among Src-PSD95-GluN2A signaling modules, and up-regulated GluN2A phosphorylation after ICH injury. Elucidation of such signaling cascades would possibly provide novel targets for ICH treatment.
authors.affiliation: Research Center for Biochemistry and Molecular Biology and Provincial Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, 221002, P. R. China.
authors.forename: Zhen-Zhen
authors.initials: ZZ
authors.lastname: Duan
authors.affiliation: Research Center for Biochemistry and Molecular Biology and Provincial Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, 221002, P. R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Research Center for Biochemistry and Molecular Biology and Provincial Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, 221002, P. R. China.
authors.forename: Feng-Ying
authors.initials: FY
authors.lastname: Li
authors.affiliation: Research Center for Biochemistry and Molecular Biology and Provincial Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, 221002, P. R. China.
authors.forename: Yi-Fei
authors.initials: YF
authors.lastname: Luan
authors.affiliation: Research Center for Biochemistry and Molecular Biology and Provincial Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, 221002, P. R. China.
authors.forename: Peng
authors.initials: P
authors.lastname: Guo
authors.affiliation: Research Center for Biochemistry and Molecular Biology and Provincial Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, 221002, P. R. China.
authors.forename: Yi-Hang
authors.initials: YH
authors.lastname: Li
authors.affiliation: Research Center for Biochemistry and Molecular Biology and Provincial Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, 221002, P. R. China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Research Center for Biochemistry and Molecular Biology and Provincial Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, 221002, P. R. China.
authors.forename: Su-Hua
authors.initials: SH
authors.lastname: Qi
mesh_terms: D000818:Animals; D002543:Cerebral Hemorrhage / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013917:Thrombin / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D014443:Tyrosine; D019061:src-Family Kinases; C000623348:F2r protein, rat; D017346:Protein Serine-Threonine Kinases; D013917:Thrombin