Identification of a Vav2-dependent mechanism for GDNF/Ret control of mesolimbic DAT trafficking
Identification of a Vav2-dependent mechanism for GDNF/Ret control of mesolimbic DAT trafficking
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DOI：
10.1038/nn.4060
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发表时间：
2015-07
影响因子：
25
通讯作者：
Shuyong Zhu;Chengjiang Zhao;Yingying Wu;Qiao-Qiao Yang-Qiao;Aiyun Shao;Tiepeng Wang;Jianfu Wu;Yanqing Yin;Yan-dong Li;Jincan Hou;Xinhua Zhang;Guomin Zhou;Xiaosong Gu;Xiaomin Wang;X. Bustelo;Jia-wei Zhou
中科院分区：
文献类型：
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作者：
Shuyong Zhu;Chengjiang Zhao;Yingying Wu;Qiao-Qiao Yang-Qiao;Aiyun Shao;Tiepeng Wang;Jianfu Wu;Yanqing Yin;Yan-dong Li;Jincan Hou;Xinhua Zhang;Guomin Zhou;Xiaosong Gu;Xiaomin Wang;X. Bustelo;Jia-wei Zhou
多巴胺（DA）的内稳态对多种大脑活动至关重要。多巴胺转运体（DAT）介导的DA再摄取是正常DA稳态的最关键机制之一。然而，大脑中DAT活性调控的分子机制仍然知之甚少。在这里，我们发现rrh家族鸟嘌呤核苷酸交换因子蛋白Vav2是DAT细胞表面表达和转运蛋白活性所必需的，转运蛋白活性由胶质细胞系来源的神经营养因子（GDNF）及其同源受体Ret调节。缺乏Vav2或ret2的小鼠显示DAT活性升高，这伴随着伏隔核细胞内选择性DA的增加。暴露于可卡因的Vav2 - / -小鼠显示DAT活性降低和行为可卡因反应减弱。我们的数据表明，Vav2是体内数据传输的决定因素，并有助于维持边缘DA神经元末端的DA稳态。
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 eitherVav2orRetdisplayed 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 traffickingin vivoand contributes to the maintenance of DA homeostasis in limbic DA neuron terminals.