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J. Neurosci. 28 (28): 7040-7046

Copyright © 2008 by the Society for Neuroscience.

Brief Communications

Anomalous Dopamine Release Associated with a Human Dopamine Transporter Coding Variant

Michelle S. Mazei-Robison,1 * Erica Bowton,2 * Marion Holy,4 Martin Schmudermaier,4 Michael Freissmuth,4 Harald H. Sitte,4 Aurelio Galli,2,3 {dagger} , and Randy D. Blakely1,3 {dagger}

Departments of 1Pharmacology and 2Molecular Physiology and Biophysics and 3Center for Molecular Neuroscience and Kennedy Center for Research on Human Development, Vanderbilt University Medical Center, Nashville, Tennessee 37232-8548, and 4Institute of Pharmacology, Center for Biomolecular Medicine and Pharmacology, Medical University Vienna, A-1090 Vienna, Austria

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, Email: 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: Email: aurelio.galli{at}vanderbilt.edu

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.

Key Words: dopamine • transport • attention deficit hyperactivity disorder • amphetamine • methylphenidate • mutation

Received for publication Feb. 1, 2008. Revision received May 26, 2008. Accepted for publication May 27, 2008.

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, Email: 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: Email: aurelio.galli{at}vanderbilt.edu

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