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D₂ Receptors Regulate Dopamine Transporter Function via an Extracellular Signal-Regulated Kinases 1 and 2-Dependent and Phosphoinositide 3 Kinase-Independent Mechanism

Integrative Neuroscience Section, National Institute on Drug Abuse Intramural Research Program/National Institutes of Health/Department of Health and Human Services, Baltimore, Maryland. (E.A.B., B.K., V.J., M.O., A.Z., T.S.S.); Department of Neurosciences, Division of Neuroscience Research, Medical University of South Carolina, Charleston, South Carolina (L.D.J., S.R.); Center for Molecular Recognition and Departments of Psychiatry and Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York (Y.H., N.S., E.U., J.A.J.); and Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, New York (I.G., L.A.D.)

The dopamine transporter (DAT) terminates dopamine (DA) neurotransmission by reuptake of DA into presynaptic neurons. Regulation of DA uptake by D₂ dopamine receptors (D₂R) has been reported. The high affinity of DA and other DAT substrates for the D₂R, however, has complicated investigation of the intracellular mechanisms mediating this effect. The present studies used the fluorescent DAT substrate, 4-[4-(diethylamino)-styryl]-N-methylpyridinium iodide (ASP⁺) with live cell imaging techniques to identify the role of two D₂R-linked signaling pathways, extracellular signal-regulated kinases 1 and 2 (ERK1/2), and phosphoinositide 3 kinase (PI3K) in mediating D₂R regulation of DAT. Addition of the D₂/D₃ receptor agonist quinpirole (0.1–10 µM) to human embryonic kidney cells coexpressing human DAT and D₂ receptor (short splice variant, D_2SR) induced a rapid, concentration-dependent and pertussis toxin-sensitive increase in ASP⁺ accumulation. The D₂/D₃ agonist (S)-(+)-(4aR, 10bR)-3,4,4a, 10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol hydrochloride (PD128907) also increased ASP⁺ accumulation. D_2SR activation increased phosphorylation of ERK1/2 and Akt, a major target of PI3K. The mitogen-activated protein kinase kinase inhibitor 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059) prevented the quinpirole-evoked increase in ASP⁺ accumulation, whereas inhibition of PI3K was without effect. Fluorescence flow cytometry and biotinylation studies revealed a rapid increase in DAT cell-surface expression in response to D₂R stimulation. These experiments demonstrate that D_2SR stimulation increases DAT cell surface expression and therefore enhances substrate clearance. Furthermore, they show that the increase in DAT function is ERK1/2-dependent but PI3K-independent. Our data also suggest the possibility of a direct physical interaction between DAT and D₂R. Together, these results suggest a novel mechanism by which D_2SRautoreceptors may regulate DAT in the central nervous system.

Address correspondence to: Dr. Toni S. Shippenberg, Integrative Neuroscience Section, NIDA IRP/NIH/DHHS, 333 Cassell Dr., Baltimore, MD 21224. E-mail: tshippen{at}intra.nida.nih.gov

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