Dysregulation of Dopamine Transporters via Dopamine D2 Autoreceptors Triggers Anomalous Dopamine Efflux Associated with Attention-Deficit Hyperactivity Disorder
- Erica Bowton1,4,
- Christine Saunders2,
- Kevin Erreger1,
- Dhananjay Sakrikar4,
- Heinrich J. Matthies1,
- Namita Sen5,6,7,
- Tammy Jessen2,
- Roger J. Colbran1,
- Marc G. Caron8,
- Jonathan A. Javitch5,6,7,
- Randy D. Blakely2,3,4, and
- Aurelio Galli1,2,4
- 1Departments of Molecular Physiology & Biophysics,
- 2Pharmacology, and
- 3Psychiatry and
- 4Center for Molecular Neuroscience, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-8548,
- 5Departments of Psychiatry and
- 6Pharmacology and
- 7Center for Molecular Recognition, College of Physicians and Surgeons, Columbia University, New York, New York 10032, and
- 8Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710
- Correspondence should be addressed to Aurelio Galli, Room 7124, Medical Research Building III, Center for Molecular Neuroscience, Vanderbilt University School of Medicine, Nashville, TN 37232-8548. aurelio.galli{at}vanderbilt.edu
Abstract
The neurotransmitter dopamine (DA) modulates brain circuits involved in attention, reward, and motor activity. Synaptic DA homeostasis is primarily controlled via two presynaptic regulatory mechanisms, DA D2 receptor (D2R)-mediated inhibition of DA synthesis and release, and DA transporter (DAT)-mediated DA clearance. D2Rs can physically associate with DAT and regulate DAT function, linking DA release and reuptake to a common mechanism. We have established that the attention-deficit hyperactivity disorder-associated human DAT coding variant Ala559Val (hDAT A559V) results in anomalous DA efflux (ADE) similar to that caused by amphetamine-like psychostimulants. Here, we show that tonic activation of D2R provides support for hDAT A559V-mediated ADE. We determine in hDAT A559V a pertussis toxin-sensitive, CaMKII-dependent phosphorylation mechanism that supports D2R-driven DA efflux. These studies identify a signaling network downstream of D2R activation, normally constraining DA action at synapses, that may be altered by DAT mutation to impact risk for DA-related disorders.
- Copyright © 2010 the authors 0270-6474/10/306048-10$15.00/0
