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 D(2) receptor (D(2)R)-mediated inhibition of DA synthesis and release, and DA transporter (DAT)-mediated DA clearance. D(2)Rs 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 D(2)R provides support for hDAT A559V-mediated ADE. We determine in hDAT A559V a pertussis toxin-sensitive, CaMKII-dependent phosphorylation mechanism that supports D(2)R-driven DA efflux. These studies identify a signaling network downstream of D(2)R activation, normally constraining DA action at synapses, that may be altered by DAT mutation to impact risk for DA-related disorders.
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Authors | Erica Bowton, Christine Saunders, Kevin Erreger, Dhananjay Sakrikar, Heinrich J Matthies, Namita Sen, Tammy Jessen, Roger J Colbran, Marc G Caron, Jonathan A Javitch, Randy D Blakely, Aurelio Galli |
Journal | The Journal of neuroscience : the official journal of the Society for Neuroscience
(J Neurosci)
Vol. 30
Issue 17
Pg. 6048-57
(Apr 28 2010)
ISSN: 1529-2401 [Electronic] United States |
PMID | 20427663
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Dopamine Plasma Membrane Transport Proteins
- Neurotransmitter Agents
- Receptors, Dopamine D2
- Pertussis Toxin
- Calcium-Calmodulin-Dependent Protein Kinase Type 2
- Dopamine
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Topics |
- Animals
- Attention Deficit Disorder with Hyperactivity
(metabolism)
- Brain
(drug effects, physiology)
- Calcium-Calmodulin-Dependent Protein Kinase Type 2
(metabolism)
- Cell Line
- Dopamine
(metabolism)
- Dopamine Plasma Membrane Transport Proteins
(genetics, metabolism)
- Genetic Variation
- Humans
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Neurons
(drug effects, physiology)
- Neurotransmitter Agents
(pharmacology)
- Pertussis Toxin
(pharmacology)
- Phosphorylation
- Receptors, Dopamine D2
(metabolism)
- Signal Transduction
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