Dysregulation of dopamine transporters via dopamine D2 autoreceptors triggers anomalous dopamine efflux associated with attention-deficit hyperactivity disorder.
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.
Bowton
Erica
E
Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-8548, USA.
Saunders
Christine
C
Erreger
Kevin
K
Sakrikar
Dhananjay
D
Matthies
Heinrich J
HJ
Sen
Namita
N
Jessen
Tammy
T
Colbran
Roger J
RJ
Caron
Marc G
MG
Javitch
Jonathan A
JA
Blakely
Randy D
RD
Galli
Aurelio
A
D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002460:Cell Line; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D014644:Genetic Variation; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018377:Neurotransmitter Agents / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D010766:Phosphorylation; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D015398:Signal Transduction
D050483:Dopamine Plasma Membrane Transport Proteins; D018377:Neurotransmitter Agents; D017448:Receptors, Dopamine D2; D037342:Pertussis Toxin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D004298:Dopamine