PMID- 28497343 OWN - NLM STAT- MEDLINE DCOM- 20180807 LR - 20220317 IS - 1573-6903 (Electronic) IS - 0364-3190 (Linking) VI - 42 IP - 10 DP - 2017 Oct TI - BDNF Contributes to Spinal Long-Term Potentiation and Mechanical Hypersensitivity Via Fyn-Mediated Phosphorylation of NMDA Receptor GluN2B Subunit at Tyrosine 1472 in Rats Following Spinal Nerve Ligation. PG - 2712-2729 LID - 10.1007/s11064-017-2274-0 [doi] AB - Previously we have demonstrated that brain-derived neurotrophic factor (BDNF) contributes to spinal long-term potentiation (LTP) and pain hypersensitivity through activation of GluN2B-containing N-methyl-D-aspartate (GluN2B-NMDA) receptors in rats following spinal nerve ligation (SNL). However, the molecular mechanisms by which BDNF impacts upon GluN2B-NMDA receptors and spinal LTP still remain unclear. In this study, we first documented that Fyn kinase-mediated phosphorylation of GluN2B subunit at tyrosine 1472 (pGluN2B(Y1472)) was involved in BDNF-induced spinal LTP and pain hypersensitivity in intact rats. Second, we revealed a co-localization of Fyn and GluN2B-NMDA receptor in cultured dorsal horn neurons, implying that Fyn is a possible intermediate kinase linking BDNF/TrkB signaling with GluN2B-NMDA receptors in the spinal dorsal horn. Furthermore, we discovered that both SNL surgery and intrathecal active Fyn could induce an increased expression of dorsal horn pGluN2B(Y1472), as well as pain hypersensitivity in response to von Frey filaments stimuli; and more importantly, all these actions were effectively abrogated by pre-treatment with either PP2 or ifenprodil to respectively inhibit Fyn kinase and GluN2B-NMDA receptors activity. Moreover, we found that intrathecal administration of BDNF scavenger TrkB-Fc prior to SNL surgery, could prevent the nerve injury-induced increase of both pFyn(Y420) and pGluN2B(Y1472) expression, and also inhibit the mechanical allodynia in neuropathic rats. Collectively, these results suggest that Fyn kinase-mediated pGluN2B(Y1472) is critical for BDNF-induced spinal LTP and pain hypersensitivity in SNL rats. Therefore, the BDNF-Fyn-GluN2B signaling cascade in the spinal dorsal horn may constitute a key mechanism underlying central sensitization and neuropathic pain development after peripheral nerve injury. FAU - Li, Song AU - Li S AD - Neuroscience Research Institute, Peking University, 38 Xue-Yuan Road, Hai-Dian District, Beijing, 100191, China. AD - Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, China. FAU - Cai, Jie AU - Cai J AD - Neuroscience Research Institute, Peking University, 38 Xue-Yuan Road, Hai-Dian District, Beijing, 100191, China. AD - Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, China. FAU - Feng, Zhi-Bo AU - Feng ZB AD - Department of Anatomy, Xinxiang Medical University, Xinxiang, Henan, China. FAU - Jin, Zi-Run AU - Jin ZR AD - Neuroscience Research Institute, Peking University, 38 Xue-Yuan Road, Hai-Dian District, Beijing, 100191, China. AD - Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, China. FAU - Liu, Bo-Heng AU - Liu BH AD - Neuroscience Research Institute, Peking University, 38 Xue-Yuan Road, Hai-Dian District, Beijing, 100191, China. AD - Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, China. FAU - Zhao, Hong-Yan AU - Zhao HY AD - Neuroscience Research Institute, Peking University, 38 Xue-Yuan Road, Hai-Dian District, Beijing, 100191, China. AD - Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, China. FAU - Jing, Hong-Bo AU - Jing HB AD - Neuroscience Research Institute, Peking University, 38 Xue-Yuan Road, Hai-Dian District, Beijing, 100191, China. AD - Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, China. FAU - Wei, Tian-Jiao AU - Wei TJ AD - Neuroscience Research Institute, Peking University, 38 Xue-Yuan Road, Hai-Dian District, Beijing, 100191, China. AD - Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, China. FAU - Yang, Guan-Nan AU - Yang GN AD - Neuroscience Research Institute, Peking University, 38 Xue-Yuan Road, Hai-Dian District, Beijing, 100191, China. AD - Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, China. FAU - Liu, Ling-Yu AU - Liu LY AD - Neuroscience Research Institute, Peking University, 38 Xue-Yuan Road, Hai-Dian District, Beijing, 100191, China. AD - Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, China. FAU - Cui, Yan-Jun AU - Cui YJ AD - Department of Internal Medicine, Peking University Hospital, Beijing, 100871, China. cyj@pku.edu.cn. FAU - Xing, Guo-Gang AU - Xing GG AD - Neuroscience Research Institute, Peking University, 38 Xue-Yuan Road, Hai-Dian District, Beijing, 100191, China. ggxing@bjmu.edu.cn. AD - Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, China. ggxing@bjmu.edu.cn. AD - Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, Peking University, Beijing, China. ggxing@bjmu.edu.cn. LA - eng GR - 81671085/National Natural Science Foundation of China/ GR - 81371237/National Natural Science Foundation of China/ PT - Journal Article DEP - 20170511 PL - United States TA - Neurochem Res JT - Neurochemical research JID - 7613461 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (NR2B NMDA receptor) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 42HK56048U (Tyrosine) RN - EC 2.7.10.2 (Fyn protein, rat) RN - EC 2.7.10.2 (Proto-Oncogene Proteins c-fyn) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Hyperalgesia/metabolism MH - Long-Term Potentiation/drug effects/*physiology MH - Male MH - Neuralgia/metabolism MH - Peripheral Nerve Injuries/metabolism MH - Phosphorylation MH - Proto-Oncogene Proteins c-fyn/*metabolism MH - Rats, Sprague-Dawley MH - Receptors, N-Methyl-D-Aspartate/*metabolism MH - Spinal Nerves/metabolism MH - Tyrosine/metabolism OTO - NOTNLM OT - Brain-derived neurotrophic factor OT - Fyn OT - GluN2B-containing NMDA receptor OT - Long-term potentiation OT - Neuropathic pain OT - Spinal dorsal horn EDAT- 2017/05/13 06:00 MHDA- 2018/08/08 06:00 CRDT- 2017/05/13 06:00 PHST- 2016/12/15 00:00 [received] PHST- 2017/04/18 00:00 [accepted] PHST- 2017/04/01 00:00 [revised] PHST- 2017/05/13 06:00 [pubmed] PHST- 2018/08/08 06:00 [medline] PHST- 2017/05/13 06:00 [entrez] AID - 10.1007/s11064-017-2274-0 [pii] AID - 10.1007/s11064-017-2274-0 [doi] PST - ppublish SO - Neurochem Res. 2017 Oct;42(10):2712-2729. doi: 10.1007/s11064-017-2274-0. Epub 2017 May 11.