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J Neurosci. 2010 Apr 28;30(17):6048-57. doi: 10.1523/JNEUROSCI.5094-09.2010.

Dysregulation of dopamine transporters via dopamine D2 autoreceptors triggers anomalous dopamine efflux associated with attention-deficit hyperactivity disorder.

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  • 1Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-8548, USA.


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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