QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.106.023952v1 70/2/542    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kahlig, K. M. Articles by Galli, A. Search for Related Content PubMed PubMed Citation Articles by Kahlig, K. M. Articles by Galli, A.

Regulation of Dopamine Transporter Trafficking by Intracellular Amphetamine

Department of Molecular Physiology and Biophysics, Center for Molecular Neuroscience, Vanderbilt University, Nashville, Tennessee (K.M.K., B.J.L., Y.W., A.G.); Molecular Neuropharmacology Group, Department of Pharmacology, the Panum Institute, University of Copenhagen, Copenhagen, Denmark (C.J.L.; U.G.); and Departments of Psychiatry and Pharmacology, Center for Molecular Recognition, College of Physicians and Surgeons, Columbia University, New York, New York (J.A.J.)

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. Coadministration of Zn²⁺ and AMPH consistently 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 down-regulation and that an increase of intracellular AMPH is an essential component of DAT redistribution.

This article has been cited by other articles:

				K. M. Kahlig, T. H. Rhodes, M. Pusch, T. Freilinger, J. M. Pereira-Monteiro, M. D. Ferrari, A. M. J. M. van den Maagdenberg, M. Dichgans, and A. L. George Jr. Divergent sodium channel defects in familial hemiplegic migraine PNAS, July 15, 2008; 105(28): 9799 - 9804. [Abstract] [Full Text] [PDF]

				W. C. Samms, R. P. Perera, D. S. Wimalasena, and K. Wimalasena Perturbation of Dopamine Metabolism by 3-Amino-2-(4'-halophenyl)propenes Leads to Increased Oxidative Stress and Apoptotic SH-SY5Y Cell Death Mol. Pharmacol., September 1, 2007; 72(3): 744 - 752. [Abstract] [Full Text] [PDF]