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Review
. 2009 Jun;20(4):411-7.
doi: 10.1016/j.semcdb.2009.01.004. Epub 2009 Jan 22.

Trafficking of dopamine transporters in psychostimulant actions

Nancy R Zahniser  1 , Alexander Sorkin
Affiliations
Review

Trafficking of dopamine transporters in psychostimulant actions

Nancy R Zahniser et al. Semin Cell Dev Biol. 2009 Jun.

Abstract

Brain dopamine (DA) plays a pivotal role in drug addiction. Since the plasma membrane DA transporter (DAT) is critical for terminating DA neurotransmission, it is important to understand how DATs are regulated and this regulation impacts drug addiction. The number of cell surface DATs is controlled by constitutive and regulated endocytic trafficking. Psychostimulants impact this trafficking. Amphetamines, DAT substrates, cause rapid up-regulation and slower down-regulation of DAT whereas cocaine, a DAT inhibitor, increases surface DATs. Recent reports have begun to elucidate the molecular mechanisms of these psychostimulant effects and link changes in DAT trafficking to psychostimulant-induced reward/reinforcement in animal models.

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Figures

Figure 1
Figure 1. Molecular determinants of DAT involved in the regulation of its intracellular trafficking
Schematic structure of DAT based on the structure of the homologous leucine transporter [79] is shown. Three putative sites of N-glycosylation in EL2 are shown in “black”. Residues in the carboxyl-terminus important for the ER exit of DAT are shown in “orange”. The PDZ domain binding motif is shown in “black”. The region of DAT proposed to be important for the constitutive endocytosis is shown in “green”. Lysine residues that are known to be ubiquitinated are shown in “blue”.
Figure 2
Figure 2. Hypothetic model of DAT trafficking in DA neurons
Newly-synthesized DAT is N-glycosylated in the Golgi apparatus (G), and transported from the Golgi to the plasma membrane in the somatodendritic compartment of DA neurons. DAT travels to distal axons by lateral movement in the plane of the plasma membrane or by transport vesicles. In the somatodendritic compartment the activation of PKC results in NEDD4-2-mediated ubiquitination of DAT. PKC activation can facilitate NEDD4-2–mediated ubiquitination of DAT either by phosphorylating DAT or DAT-interacting proteins, or by activating NEDD4-2. Ubiquitinated DAT is recruited into clathrin-coated pits (CCP) by means of interaction with UBD-containing proteins, such as Eps15/Eps15R and epsin, that are bound to AP-2 and clathrin in coated pits. After internalization via clathrin-coated vesicles (CCV) to early and recycling endosomes (EE/RE), DAT is sorted in MVB to lysosomes (Lys), presumably by the mechanism mediated by ESCRT complexes. In the distal axonal processes, DAT is internalized and recycled in a manner similar to that in neuronal soma, although there is likely no sorting to late endosomes within the axonal varicosities lacking late endosomes and lysosomes. SV, synaptic vesicles.
Figure 3
Figure 3. Effects of amphetamines and cocaine on the endocytic trafficking of DAT
(A) DAT-mediated transport of amphetamines into the cell is required for amphetamine-induced elevation in intracellular Ca2+, activation of PKC and CaMKII, and inhibition of Akt activity. All or some of these events result in acceleration of DAT internalization and/or reduction of DAT recycling, ultimately leading to a slower (30–120 min) down-regulation of the surface pool of DATs and accumulation of DATs in early and recycling endosomes (EEs/REs). Amphetamine also causes rapid, transient (≤1 min) up-regulation of the surface pool of DATs by unknown mechanisms, which may involve DAT transport from REs to the plasma membrane. (B) Inhibition of DAT by cocaine results in partial redistribution of DATs from endosomes to the plasma membrane by unknown mechanisms.
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