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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}vanderbilt.edu; 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}vanderbilt.edu
  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.

Abstract

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

Citation:

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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