Journal
NATURE NEUROSCIENCE
Volume 18, Issue 8, Pages 1084-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nn.4060
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Funding
- National Key Basic Research Program of China [2015CB553500, 2011CB504102]
- Natural Science Foundation of China [31123002, 31321091, 30621130075]
- Beijing Institute for Brain Disorders [BIBD-PXM2013_014226_07_000084]
- Strategic Priority Research Program (B) of the Chinese Academy of Sciences [XDB01020300]
- Spanish Ministry of Economy and Competitiveness [SAF2009-07172, SAF2012-3171, RD06/0020/0001, RD12/0036/0002]
- Castilla-Leon Autonomous Government [CSI101U13]
- Spanish Association of Science Communication
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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.
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