Regulation of the dopamine transporter

Dopaminergic signaling in the brain is primarily modulated by dopamine transporters (DATs), which actively translocate extraneuronal dopamine back into dopaminergic neurons. Transporter proteins are highly dynamic, continuously trafficking between plasmalemmal and endosomal membranes. Changes in DAT...

Full description

Saved in:
Bibliographic Details
Published in:Annals of the New York Academy of Sciences 2010-02, Vol.1187 (1), p.316-340
Main Authors: Schmitt, Kyle C., Reith, Maarten E. A.
Format: Article
Language:English
Subjects:
amphetaminergic substrates
Amphetamines
Cocaine
Dopamine
dopamine transporter
internalization
Ligands
MDMA
Medical research
methamphetamine
regulation
trafficking
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Dopaminergic signaling in the brain is primarily modulated by dopamine transporters (DATs), which actively translocate extraneuronal dopamine back into dopaminergic neurons. Transporter proteins are highly dynamic, continuously trafficking between plasmalemmal and endosomal membranes. Changes in DAT membrane trafficking kinetics can rapidly regulate dopaminergic tone by altering the number of transporters present at the cell surface. Various psychostimulant DAT ligands—acting either as amphetamine‐like substrates or cocaine‐like nontranslocated inhibitors—affect transporter trafficking, triggering rapid insertion or removal of plasmalemmal DATs. In this review, we focus on the effects of psychostimulants of addiction (particularly d‐methamphetamine and cocaine) on DAT regulation and membrane trafficking, with an emphasis on how these drugs may influence intracellular signaling cascades and transporter‐associated scaffolding proteins to affect DAT regulation. In addition, we consider involvement of presynaptic receptors for dopamine and other ligands in DAT regulation. Finally, we discuss possible implications of transporter regulation to the putative toxicity of several substituted amphetamine derivatives commonly used as recreational drugs, as well as to the design of therapeutics for cocaine addiction.
ISSN:0077-8923
1749-6632
DOI:10.1111/j.1749-6632.2009.05148.x