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Anomalous Dopamine Release Associated with a Human Dopamine Transporter Coding Variant

J. Neurosci., 9 July 2008
Vol. 28, Issue 28, p. 7040-7046
DOI: 10.1523/JNEUROSCI.0473-08.2008

Anomalous Dopamine Release Associated with a Human Dopamine Transporter Coding Variant

  1. Michelle S. Mazei-Robison 1 ,*,
  2. Erica Bowton 2 ,*,
  3. Marion Holy 4 ,
  4. Martin Schmudermaier 4 ,
  5. Michael Freissmuth 4 ,
  6. Harald H. Sitte 4 ,
  7. Aurelio Galli 2 , 3 , , and
  8. Randy D. Blakely 1 , 3 ,
  1. Departments of 1Pharmacology and
  2. 2Molecular Physiology and Biophysics and
  3. 3Center for Molecular Neuroscience and Kennedy Center for Research on Human Development, Vanderbilt University Medical Center, Nashville, Tennessee 37232-8548, and
  4. 4Institute of Pharmacology, Center for Biomolecular Medicine and Pharmacology, Medical University Vienna, A-1090 Vienna, Austria
  1. Correspondence should be addressed to either of the following: Randy D. Blakely, Suite 7140, MRBIII, Center for Molecular Neuroscience, Vanderbilt University School of Medicine, 465 21st Avenue South, Nashville, TN 37232-8548, randy.blakely{at}; or Aurelio Galli, Suite 7124, MRBIII, Center for Molecular Neuroscience, Vanderbilt University School of Medicine, 465 21st Avenue South, Nashville, TN 37232-8548, E-mail: aurelio.galli{at}
  1. *M.S.M.-R. and E.B. contributed equally to this work.

  2. A.G. and R.D.B. contributed equally to this work.


Dopamine (DA) signaling at synapses is tightly coordinated through opposing mechanisms of vesicular fusion-mediated DA release and transporter-mediated DA clearance. Altered brain DA signaling is suspected to underlie multiple brain disorders, including schizophrenia, Parkinson's disease, bipolar disorder, and attention-deficit hyperactivity disorder (ADHD). We identified a pedigree containing two male children diagnosed with ADHD who share a rare human DA transporter (DAT; SLC6A3) coding variant, Ala559Val. Among >1000 control and affected subjects, the Val559 variant has only been isolated once previously, in a female subject with bipolar disorder. Although hDAT Ala559Val supports normal DAT protein and cell surface expression, as well as normal DA uptake, the variant exhibits anomalous DA efflux from DA-loaded cells. We also demonstrate that hDAT Ala599Val exhibits increased sensitivity to intracellular Na+, but not intracellular DA, and displays exaggerated DA efflux at depolarized potentials. Remarkably, the two most common ADHD medications, amphetamine and methylphenidate, both block hDAT Ala559Val-mediated DA efflux, whereas these drugs have opposite actions at wild-type hDAT. Our findings reveal that DA efflux, typically associated with amphetamine-like psychostimulants, can be produced through a heritable change in hDAT structure. Because multiple gene products are known to coordinate to support amphetamine-mediated DA efflux, the properties of hDAT Ala559Val may have broader significance in identifying a new mechanism through which DA signaling disorders arise. Additionally, they suggest that block of inappropriate neurotransmitter efflux may be an unsuspected mechanism supporting the therapeutic actions of existing transporter-directed medications.

  • dopamine
  • transport
  • attention deficit hyperactivity disorder
  • amphetamine
  • methylphenidate
  • mutation


M. S. Mazei-Robison, E. Bowton, M. Holy, M. Schmudermaier, M. Freissmuth, H. H. Sitte, A. Galli, and R. D. Blakely, Anomalous Dopamine Release Associated with a Human Dopamine Transporter Coding Variant. J. Neurosci. 28, 7040-7046 (2008).

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