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Papers In Press, published online ahead of print December 29, 2003
Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232
Corresponding Author: Aurelio.Galli{at}Vanderbilt.edu
Dopaminergic neurotransmission is fine-tuned by 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 DAT’s function 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 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 reduction of hDAT transport capacity results from the removal of active hDAT from the plasma membrane.
J. Biol. Chem, 10.1074/jbc.M303976200
Submitted on April 15, 2003
Revised on December 11, 2003
Accepted on December 22, 2003
Amphetamine regulation of dopamine transport: Combined measurements of transporter currents and transporter imaging support the endocytosis of an active carrier
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