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

Bowton E, Saunders C, Erreger K, Sakrikar D, Matthies HJ, Sen N, Jessen T, Colbran RJ, Caron MG, Javitch JA, Blakely RD, Galli A
J Neurosci. 2010 30 (17): 6048-57

PMID: 20427663 · PMCID: PMC2881830 · DOI:10.1523/JNEUROSCI.5094-09.2010

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.

MeSH Terms (19)

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

Connections (4)

This publication is referenced by other Labnodes entities: