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J. Biol. Chem., Vol. 279, Issue 10, 8966-8975, March 5, 2004

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Amphetamine Regulation of Dopamine Transport

COMBINED MEASUREMENTS OF TRANSPORTER CURRENTS AND TRANSPORTER IMAGING SUPPORT THE ENDOCYTOSIS OF AN ACTIVE CARRIER^*

Kristopher M. Kahlig, Jonathan A. Javitch, and Aurelio Galli¶

From the Department of Molecular Physiology and Biophysics, Center for Molecular Neuroscience, Vanderbilt University, Nashville, Tennessee 37232-8548 and the Departments of Psychiatry and Pharmacology, Center for Molecular Recognition, College of Physicians and Surgeons, Columbia University, New York, New York 10032

Dopaminergic neurotransmission is fine-tuned by the rate of removal of dopamine (DA) from the extracellular space via the Na⁺/Cl^--dependent DA transporter (DAT). DAT is a target of psychostimulants such as amphetamine (AMPH) and cocaine. Previously, we reported that AMPH redistributes the human DAT away from the cell surface. This process was associated with a reduction in transport capacity. This loss of transport capacity may result either from a modification of the function of DAT that is independent of its cell surface redistribution and/or from a reduction in the number of active transporters at the plasma membrane that results from DAT trafficking. To discriminate between these possibilities, we stably transfected HEK-293 cells with a yellow fluorescent protein (YFP)-tagged human DAT (hDAT cells). In hDAT cells, acute exposure to AMPH induced a time-dependent loss of hDAT activity. By coupling confocal imaging with patch-clamp whole-cell recordings, we have demonstrated for the first time that the loss of AMPH-induced hDAT activity temporally parallels the accumulation of intracellular hDAT. In addition, presteady-state current analysis revealed a cocaine-sensitive, voltage-dependent capacitance current that correlated with the level of transporter membrane expression and in turn served to monitor the AMPH-induced trafficking of hDAT. We found that the decrease in hDAT cell surface expression induced by AMPH was not paralleled by changes in the ability of the single transporter to carry charges. Quasi-stationary noise analysis of the AMPH-induced hDAT currents revealed that the unitary transporter current remained unaltered during the loss of hDAT membrane expression. Taken together, these data strongly suggest that the AMPH-induced reduction of hDAT transport capacity results from the removal of active hDAT from the plasma membrane.

Received for publication, April 15, 2003 , and in revised form, December 11, 2003.

^* This work was supported by a National Alliance for Research on Schizophrenia and Depression Young Investigator Award (to A. G.) and by National Institutes of Health Grants DA13975 and DA14684 (to A. G.) and MH57324 and DA11495 (to J. A. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Molecular Physiology and Biophysics, Center for Molecular Neuroscience, Vanderbilt University, 465 21st Ave. South, Nashville, TN 37232-8548. Tel.: 615-936-3891; Fax: 615-936-3745; E-mail: Aurelio.Galli{at}vanderbilt.edu.

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