@article{8c38a12da0dc491e8cdf2e238aadac88,
title = "Kinesin-1 Regulates Extrasynaptic Targeting of NMDARs and Neuronal Vulnerability Toward Excitotoxicity",
abstract = "N-methyl-D-aspartate (NMDA)receptor (NMDAR)is highly compartmentalized in neurons, and its dysfunction has been implicated in various neuropsychiatric and neurodegenerative disorders. Recent failure to exploit NMDAR antagonization as a potential therapeutic target has driven the need to identify molecular mechanisms that regulate NMDAR compartmentalization. Here, we report that the reduction of Kif5b, the heavy chain of kinesin-1, protected neurons against NMDA-induced excitotoxicity and ischemia-provoked neurodegeneration. Direct binding of kinesin-1 to the GluN2B cytoplasmic tails regulated the levels of NMDAR at extrasynaptic sites and the subsequent influx of calcium mediated by extrasynaptic NMDAR by regulating the insertion of NMDARs into neuronal surface. Transient increase of Kif5b restored the surface levels of NMDAR and the decreased neuronal susceptibility to NMDA-induced excitotoxicity. The expression of Kif5b was repressed in cerebral ischemia preconditioning. Our findings reveal that kinesin-1 regulates extrasynaptic NMDAR targeting and signaling, and the reduction of kinesin-1 could be exploited to defer neurodegeneration.",
keywords = "Cellular Neuroscience, Molecular Neuroscience, Neuroscience",
author = "Raozhou Lin and Zhigang Duan and Haitao Sun and Fung, {Man Lung} and Hansen Chen and Jing Wang and Lau, {Chi Fai} and Di Yang and Yu Liu and Yanxiang Ni and Zai Wang and Ju Cui and Wutian Wu and Yung, {Wing Ho} and Chan, {Ying Shing} and Lo, {Amy C.Y.} and Jun Xia and Jiangang Shen and Huang, {Jian Dong}",
note = "Funding Information: We thank Dr. Jianhong Luo for providing the GFP-GluN2B plasmid, Dr. Anne Stephenson for providing the GluN1-1a plasmid, and Dr. Scott Brady and Dr. Gerardo Morfini for providing the mouse Kif5b cDNA. We thank Dr. Jing Guo, Mr. Cyril Lai, and Miss Jess Chan for their technical support for the confocal microscopy. We thank Dr. Yue Zhuo (Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences) for helping in the characterization of protein-protein interactions. This study was supported by Shenzhen Peacock project ( KQTD2015033117210153 ) and Shenzhen Science and Technology Innovation Committee Basic Science Research Grant ( JCYJ20150629151046896 ), the University Grants Committee of Hong Kong ( AoE/M-04/04 ), Hong Kong Research Grants Council ( HKU 767012/04M , HKU 768113M , HKU 17127015/05M , HKUST10/CRF/12R ), and Hong Kong Scholars Program (No. XJ2016055). Funding Information: We thank Dr. Jianhong Luo for providing the GFP-GluN2B plasmid, Dr. Anne Stephenson for providing the GluN1-1a plasmid, and Dr. Scott Brady and Dr. Gerardo Morfini for providing the mouse Kif5b cDNA. We thank Dr. Jing Guo, Mr. Cyril Lai, and Miss Jess Chan for their technical support for the confocal microscopy. We thank Dr. Yue Zhuo (Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences)for helping in the characterization of protein-protein interactions. This study was supported by Shenzhen Peacock project (KQTD2015033117210153)and Shenzhen Science and Technology Innovation Committee Basic Science Research Grant (JCYJ20150629151046896), the University Grants Committee of Hong Kong (AoE/M-04/04), Hong Kong Research Grants Council (HKU 767012/04M, HKU 768113M, HKU 17127015/05M, HKUST10/CRF/12R), and Hong Kong Scholars Program (No. XJ2016055). The work presented here was carried out in collaboration with all authors. J.D.H. directed and coordinated the study. R.L. designed and conducted the experiments and analyzed the data. Z.D. performed the GST pull-down experiments and rescue experiments. J.W. performed the pilot experiments. M.-L.F. C.-F.L. and Y.L. conducted the NO measurements. D.Y. A.C.Y.L. H.C. H.S. and J. S. helped with the MCAO experiments. Y.N. Z.W. and J.C. helped with the GST pull-down experiments and animal maintenance. W.W. J.X. W.-H.Y. and Y.-S.C. provided critical comments on the project. R.L. and J.-D.H. wrote the manuscript. All authors read, commented on, and approved the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 The Author(s)",
year = "2019",
month = mar,
day = "29",
doi = "10.1016/j.isci.2019.02.009",
language = "English (US)",
volume = "13",
pages = "82--97",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier Inc.",
}