title: Dysregulation of dopamine transporters via dopamine D2 autoreceptors triggers anomalous dopamine efflux associated with attention-deficit hyperactivity disorder.
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.
authors.affiliation: Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-8548, USA.
authors.forename: Erica
authors.initials: E
authors.lastname: Bowton
authors.forename: Christine
authors.initials: C
authors.lastname: Saunders
authors.forename: Kevin
authors.initials: K
authors.lastname: Erreger
authors.forename: Dhananjay
authors.initials: D
authors.lastname: Sakrikar
authors.forename: Heinrich J
authors.initials: HJ
authors.lastname: Matthies
authors.forename: Namita
authors.initials: N
authors.lastname: Sen
authors.forename: Tammy
authors.initials: T
authors.lastname: Jessen
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Colbran
authors.forename: Marc G
authors.initials: MG
authors.lastname: Caron
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Javitch
authors.forename: Randy D
authors.initials: RD
authors.lastname: Blakely
authors.forename: Aurelio
authors.initials: A
authors.lastname: Galli
mesh_terms: 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
chemical_list: 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