D₂Receptors Regulate Dopamine Transporter Function via an Extracellular Signal-Regulated Kinases 1 and 2-Dependent and Phosphoinositide 3 Kinase-Independent Mechanism

Abstract

The dopamine transporter (DAT) terminates dopamine (DA) neurotransmission by reuptake of DA into presynaptic neurons. -(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059) prevented the quinpirole-evoked increase in ASPϩ 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 D 2 R stimulation. These experiments demonstrate that D 2S R 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 D 2 R. Together, these results suggest a novel mechanism by which D 2S R autoreceptors may regulate DAT in the central nervous system. Dopamine (DA) is the predominant catecholamine neurotransmitter in the central nervous system. Dysregulation of DA neurons has been implicated in the pathogenesis of Parkinson's disease, schizophrenia, and drug addiction (Sotnikova et al., 2006). Extracellular DA levels are primarily regulated by the DA transporter (DAT), an integral membrane protein that is a member of the Na ϩ /Cl Ϫ -dependent J.J., A.Z., and T.S.S. contributed equally to this work.

Extrastriatal dopaminergic abnormalities of DA homeostasis in Parkinson's patients with medication-induced pathological gambling: A [11C] FLB-457 and PET study

“…D2 autoreceptors have been found to associate with DAT, and support DAT trafficking (Bolan et al, 2007;Lee et al, 2007). Thus, our results are consistent with recent SPECT data showing reduced striatal DAT binding in PD patients with ICDs .…”

Serotonin Uptake Is Largely Mediated by Platelets versus Lymphocytes in Peripheral Blood Cells

“…Others have shown using ASP+, another fluorescent MPP+ analogue ( Figure S1, Supporting Information), that DAT is regulated by activation of D2 and D3 dopamine receptors. 54 Unlike dopamine, ASP+ interacts selectively with DAT versus dopamine receptors. Similarly, flow cytometry, in combination with IDT307, could be used to examine SERT/5-HT1A receptor interactions in immune cells.…”

Regulated Norepinephrine Transporter Interaction with the Neurokinin-1 Receptor Establishes Transporter Subcellular Localization

“…Signals linked to G protein-coupled receptor (GPCR) activation are also known to regulate NET (9,10). Studies have shown evidence for receptor activation regulating transporter and transporter modulation regulating receptor function (4,(11)(12)(13). These studies indicate a close interaction between GPCR and transporter proteins.…”