title: Dopamine transporter cell surface localization facilitated by a direct interaction with the dopamine D2 receptor.
abstract: Altered synaptic dopamine levels have been implicated in several neurological/neuropsychiatric disorders, including drug addiction and schizophrenia. However, it is unclear what precipitates these changes in synaptic dopamine levels. One of the key presynaptic components involved in regulating dopaminergic tone is the dopamine transporter (DAT). Here, we report that the DAT is also regulated by the dopamine D2 receptor through a direct protein-protein interaction involving the DAT amino-terminus and the third intracellular loop of the D2 receptor. This physical coupling facilitates the recruitment of intracellular DAT to the plasma membrane and leads to enhanced dopamine reuptake. Moreover, mice injected with peptides that disrupt D2-DAT interaction exhibit decreased synaptosomal dopamine uptake and significantly increased locomotor activity, reminiscent of DAT knockout mice. Our data highlight a novel mechanism through which neurotransmitter receptors can functionally modulate neurotransmitter transporters, an interaction that can affect the synaptic neurotransmitter levels in the brain.
authors: Department of Neuroscience, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada.
authors: Frank J S
authors: FJ
authors: Lee
authors: Lin
authors: L
authors: Pei
authors: Anna
authors: A
authors: Moszczynska
authors: Brian
authors: B
authors: Vukusic
authors: Paul J
authors: PJ
authors: Fletcher
authors: Fang
authors: F
authors: Liu
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D018613:Microscopy, Confocal; D021381:Protein Transport / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D017448:Receptors, Dopamine D2