Kinesin-1 Regulates Extrasynaptic Targeting of NMDARs and Neuronal Vulnerability Toward Excitotoxicity
Raozhou Lin,
Zhigang Duan,
Haitao Sun,
Man-Lung Fung,
Hansen Chen,
Jing Wang,
Chi-Fai Lau,
Di Yang,
Yu Liu,
Yanxiang Ni,
Zai Wang,
Ju Cui,
Wutian Wu,
Wing-Ho Yung,
Ying-Shing Chan,
Amy C.Y. Lo,
Jun Xia,
Jiangang Shen,
Jian-Dong Huang
Affiliations
Raozhou Lin
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
Zhigang Duan
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
Haitao Sun
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong; State Key Laboratory of Brain and Cognitive Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong; Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
Man-Lung Fung
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
Hansen Chen
School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
Jing Wang
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
Chi-Fai Lau
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
Di Yang
Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
Yu Liu
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
Yanxiang Ni
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong; Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering, Shenzhen University, Shenzhen, China
Zai Wang
Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
Ju Cui
Beijing Institute of Geriatrics, Beijing Hospital, Ministry of Health, Beijing, China
Wutian Wu
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong; GHM Institute of CNS Regeneration, Jinan University, Guangzhou, China
Wing-Ho Yung
School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong
Ying-Shing Chan
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong; State Key Laboratory of Brain and Cognitive Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
Amy C.Y. Lo
Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
Jun Xia
Division of Life Sciences, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong
Jiangang Shen
School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
Jian-Dong Huang
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong; State Key Laboratory of Brain and Cognitive Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong; HKU-Shenzhen Institute of Research and Innovation, Shenzhen, China; Shenzhen Institute of Advanced Technologies, Shenzhen, China; Corresponding author
Summary: 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. : Neuroscience; Molecular Neuroscience; Cellular Neuroscience Subject Areas: Neuroscience, Molecular Neuroscience, Cellular Neuroscience