Identification of a Vav2-dependent mechanism for GDNF/Ret control of mesolimbic DAT trafficking

Nat Neurosci. 2015 Aug;18(8):1084-93. doi: 10.1038/nn.4060. Epub 2015 Jul 6.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Cocaine / pharmacology
  • Dopamine / metabolism*
  • Dopamine Plasma Membrane Transport Proteins / metabolism*
  • Dopaminergic Neurons / metabolism*
  • Glial Cell Line-Derived Neurotrophic Factor / metabolism*
  • Homeostasis
  • Limbic System / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nucleus Accumbens / metabolism*
  • Protein Transport
  • Proto-Oncogene Proteins c-ret / metabolism*
  • Proto-Oncogene Proteins c-vav
  • Signal Transduction / physiology*


  • Dopamine Plasma Membrane Transport Proteins
  • Gdnf protein, mouse
  • Glial Cell Line-Derived Neurotrophic Factor
  • Proto-Oncogene Proteins c-vav
  • Vav2 protein, mouse
  • Proto-Oncogene Proteins c-ret
  • Ret protein, mouse
  • Cocaine
  • Dopamine