title: Identification of a Vav2-dependent mechanism for GDNF/Ret control of mesolimbic DAT trafficking.
abstract: Dopamine (DA) homeostasis is essential for a variety of brain activities. Dopamine transporter (DAT)-mediated DA reuptake is one of the most critical mechanisms for normal DA homeostasis. However, the molecular mechanisms underlying the regulation of DAT activity in the brain remain poorly understood. Here we show that the Rho-family guanine nucleotide exchange factor protein Vav2 is required for DAT cell surface expression and transporter activity modulated by glial cell line-derived neurotrophic factor (GDNF) and its cognate receptor Ret. Mice deficient in either Vav2 or Ret displayed elevated DAT activity, which was accompanied by an increase in intracellular DA selectively in the nucleus accumbens. Vav2(-/-) mice exposed to cocaine showed reduced DAT activity and diminished behavioral cocaine response. Our data demonstrate that Vav2 is a determinant of DAT trafficking in vivo and contributes to the maintenance of DA homeostasis in limbic DA neuron terminals.
authors.affiliation: Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Shuyong
authors.initials: S
authors.lastname: Zhu
authors.affiliation: 1] Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. [2] University of the Chinese Academy of Sciences, Shanghai, China.
authors.forename: Chengjiang
authors.initials: C
authors.lastname: Zhao
authors.affiliation: 1] Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. [2] University of the Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Wu
authors.affiliation: 1] Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. [2] Department of Anatomy, Histology and Embryology, Shanghai Medical School, Fudan University, Shanghai, China.
authors.forename: Qiaoqiao
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Aiyun
authors.initials: A
authors.lastname: Shao
authors.affiliation: Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Tiepeng
authors.initials: T
authors.lastname: Wang
authors.affiliation: Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Jianfu
authors.initials: J
authors.lastname: Wu
authors.affiliation: Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yandong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Jincan
authors.initials: J
authors.lastname: Hou
authors.affiliation: 1] Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. [2] Co-innovation Center of Neuroregeneration, School of Medicine, Nantong University, Nantong, China.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Anatomy, Histology and Embryology, Shanghai Medical School, Fudan University, Shanghai, China.
authors.forename: Guomin
authors.initials: G
authors.lastname: Zhou
authors.affiliation: Co-innovation Center of Neuroregeneration, School of Medicine, Nantong University, Nantong, China.
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Gu
authors.affiliation: Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas, University of Salamanca, Salamanca, Spain.
authors.forename: Xosé R
authors.identifier: 0000000193986072
authors.initials: XR
authors.lastname: Bustelo
authors.affiliation: Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism*; D006706:Homeostasis; D008032:Limbic System / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009714:Nucleus Accumbens / Q000378:metabolism*; D021381:Protein Transport; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051567:Proto-Oncogene Proteins c-vav; C490565:Vav2 protein, mouse; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse; D003042:Cocaine; D004298:Dopamine