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J. Biol. Chem., Vol. 278, Issue 24, 22168-22174, June 13, 2003
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From the
Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts School of Medicine, Worcester, Massachusetts 01604,
Program in Neuroscience, University of Massachusetts School of Medicine, Worcester, Massachusetts 01604,
¶ Interdisciplinary Graduate Program, University of Massachusetts School of Medicine, Worcester, Massachusetts 01604
The dopamine transporter (DAT) removes dopamine from the extracellular milieu and is potently inhibited by number of psychoactive drugs, including cocaine, amphetamines, and methylphenidate (Ritalin). Multiple lines of evidence demonstrate that protein kinase C (PKC) down-regulates dopamine transport, primarily by redistributing DAT from the plasma membrane to endosomal compartments, although the mechanisms facilitating transporter sequestration are not defined. Here, we demonstrate that DAT constitutively internalizes and recycles in rat pheochromocytoma (PC12) cells. Temperature blockades demonstrated basal internalization and reliance on recycling to maintain DAT cell surface levels. In contrast, recycling blockade with bafilomycin A1 significantly decreased transferrin receptor (TfR) surface expression but had no effect on DAT surface levels, suggesting that DAT and TfR traffic via distinct endosomal mechanisms. Kinetic analyses reveal robust constitutive DAT cycling to and from the plasma membrane, independent of transporter expression levels. In contrast, phorbol ester-mediated PKC activation accelerated DAT endocytosis and attenuated transporter recycling in a manner sensitive to DAT expression levels. These data demonstrate constitutive DAT trafficking and that PKC-mediated DAT sequestration is achieved by a combination of accelerated internalization and reduced recycling. Additionally, the differential sensitivity to expression level exhibited by constitutive and regulated DAT trafficking suggests that these two processes are mediated by independent cellular mechanisms.
Received for publication, February 20, 2003 , and in revised form, April 3, 2003.
* This work was supported by a National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award and by National Institutes of Health Grant R01 DA15169-01 (to H. E. M.). 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: Brudnick Neuropsychiatric Research Institute, Dept. of Psychiatry, University of Massachusetts Medical School, 303 Belmont St., Worcester, MA 01604. Tel.: 508-856-4045; Fax: 508-856-4130; E-mail: haley.melikian{at}umassmed.edu.
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