WWW.JNEUROSCI.ORG
-
The Journal of Neuroscience
QUICK SEARCH:   [advanced]


     
-


HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP
The Journal of Neuroscience, July 9, 2008, 28(28):7040-7046; doi:10.1523/JNEUROSCI.0473-08.2008

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit an eLetter
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Related articles in J. Neurosci.
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (6)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Mazei-Robison, M. S.
Right arrow Articles by Blakely, R. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mazei-Robison, M. S.
Right arrow Articles by Blakely, R. D.

 Previous Article  |  Next Article 

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

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 Feb. 1, 2008; revised May 26, 2008; accepted 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


Related articles in J. Neurosci.:

This Week in The Journal

J. Neurosci. 2008 28: i. [Full Text]  



This article has been cited by other articles:


Home page
 Mol. Pharmacol.Home page
F. Binda, C. Dipace, E. Bowton, S. D. Robertson, B. J. Lute, J. U. Fog, M. Zhang, N. Sen, R. J. Colbran, M. E. Gnegy, et al.
Syntaxin 1A Interaction with the Dopamine Transporter Promotes Amphetamine-Induced Dopamine Efflux
Mol. Pharmacol., October 1, 2008; 74(4): 1101 - 1108.
[Abstract] [Full Text] [PDF]


-
-

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help
-
Copyright 2009 by Society for Neuroscience ONLINE ISSN: 1529-2401
-