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First published on May 9, 2006; DOI: 10.1124/mol.106.023952

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Received for publication March 1, 2006.
Revised May 5, 2006.
Accepted for publication May 5, 2006.

Regulation of Dopamine Transporter Trafficking by Intracellular Amphetamine

Kristopher M. Kahlig 1, Brandon J. Lute 1, Yuqiang Wei 1, Claus J. Loland 2, Ulrik Gether 2, Jonathan A. Javitch 3, Aurelio Galli 1*

1 Vanderbilt University 2 University of Copenhagen 3 Columbia University

* Address correspondence to: E-mail: aurelio.galli{at}vanderbilt.edu

Abstract

The dopamine (DA) transporter (DAT) mediates the removal of released DA. DAT is the major molecular target responsible for the rewarding properties and abuse potential of the psychostimulant amphetamine (AMPH). AMPH has been shown to reduce the number of DATs at the cell surface, and this AMPH-induced cell surface DAT redistribution may result in long lasting changes in DA homeostasis. The molecular mechanism by which AMPH induces trafficking is not clear. Because AMPH is a substrate, we do not know whether extracellular AMPH stimulates trafficking through its interaction with DAT and subsequent alteration in DAT function, thereby triggering intracellular signaling, or whether AMPH must be transported and then act intracellularly. In agreement with our previous studies, extracellular AMPH caused cytosolic redistribution of the wild-type human DAT (WT-hDAT). However, AMPH did not induce cytosolic redistribution in an uptake-impaired hDAT (Y335A-hDAT) that still binds AMPH. The divalent cation zinc (Zn2+) inhibits WT-hDAT activity, but it restores Y335A-hDAT uptake. Consistently, co-administration of Zn2+ and AMPH reduced WT-hDAT trafficking, but stimulated cytosolic redistribution of Y335A-hDAT. Furthermore, direct intracellular application of AMPH, via a whole cell patch pipette, stimulated the trafficking of Y335A-hDAT. Taken together, these data suggest that the DAT transport cycle is not required for AMPH-induced downregulation, and that an increase of intracellular AMPH is essential component of hDAT redistribution.


Key words: Dopamine, Biogenic Amine, Amphetamines


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