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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Attention Deficit Disorder with Hyperactivity / metabolism*
  • Brain / drug effects
  • Brain / physiology
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Cell Line
  • Dopamine / metabolism*
  • Dopamine Plasma Membrane Transport Proteins / genetics
  • Dopamine Plasma Membrane Transport Proteins / metabolism*
  • Genetic Variation
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neurons / drug effects
  • Neurons / physiology
  • Neurotransmitter Agents / pharmacology
  • Pertussis Toxin / pharmacology
  • Phosphorylation
  • Receptors, Dopamine D2 / metabolism*
  • Signal Transduction

Substances

  • Dopamine Plasma Membrane Transport Proteins
  • Neurotransmitter Agents
  • Receptors, Dopamine D2
  • Pertussis Toxin
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Dopamine