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The Journal of Neuroscience, September 17, 2003, 23(24):8480-8488
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Mitogen-Activated Protein Kinase Regulates Dopamine Transporter Surface Expression and Dopamine Transport Capacity
José A. Morón,1 * Irina Zakharova,1 * Jasmine V. Ferrer,3 Gerald A. Merrill,4 Bruce Hope,1 Eileen M. Lafer,5 Zhi Cheng Lin,2 Jia Bei Wang,7 Jonathan A. Javitch,3 Aurelio Galli,6 * andToni S. Shippenberg1 * 1Behavioral Neuroscience Branch and 2Molecular Neurobiology Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland 21224, 3Center for Molecular Recognition, College of Physicians and Surgeons, Columbia University, New York, New York 10032, 4Department of Clinical Investigation, Brooke Army Medical Center, Houston, Texas 78234, Departments of 5Biochemistry and 6Pharmacology, University of Texas Health Science Center, San Antonio, Texas 78229, and 7Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201
The dopamine transporter (DAT) regulates the clearance of dopamine (DA) released into the extracellular space and is an important site on which psychostimulants act to produce their effects. Here, we show that mitogen-activated protein kinase (MAPK) regulates the transport capacity and intracellular trafficking of DAT. Incubation of striatal synaptosomes or epitope-tagged human DAT (hDAT) human embryonic kidney (HEK) 293 cells with the MAPK kinase (MEK) inhibitors 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto) butadiene and 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one decreased DA uptake in a concentration- and time-dependent manner. Kinetic studies revealed a decrease in the capacity of transport (Vmax) but no change in Km. Immunoblotting confirmed labeling of p42 and p44 MAPK in untreated striatal synaptosomes and HEK 293 cells, consistent with constitutive MAPK activation, and the inhibitors used decreased MAPK phosphorylation. Biotinylation and confocal imaging studies showed that MAPK inhibition promoted the clathrin-associated redistribution of hDAT from the plasma membrane to the cytosol. In contrast, transient transfection of hDAT-expressing cells with constitutively active MEK increased the Vmax of DA transport without altering Km. However, only a small increase in hDAT cell surface expression was seen. These data demonstrate an involvement of the MAPK cascade in regulating DAT transport capacity in striatum and that inhibition of this cascade decreases DAT cell surface expression in HEK 293 cells. Furthermore, they highlight the potential role of MAPK as a presynaptic mechanism that regulates DA signaling.
Key words: dopamine transporter; trafficking; epitope-tagged-hDAT; HEK 293 cells; MAPK; biotinylation
Received Jan 17, 2003; revised June 23, 2003; accepted June 30, 2003.
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