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J. Biol. Chem., Vol. 279, Issue 52, 54380-54386, December 24, 2004

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Parkin Increases Dopamine Uptake by Enhancing the Cell Surface Expression of Dopamine Transporter^*

Houbo Jiang, Qian Jiang, and Jian Feng

From the Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, New York 14214

Mutations of parkin, a protein-ubiquitin E3 ligase, are linked to Parkinson's disease (PD). Although a variety of parkin substrates have been identified, none of these is selectively expressed in dopaminergic neurons, whose degeneration plays a critical role in PD. Here we show that parkin significantly increased dopamine uptake in the human dopaminergic neuroblastoma cell line SH-SY5Y. This effect was accompanied by increased V_max of dopamine uptake and unchanged K_m. Consistent with this, increased binding sites for dopamine transporter (DAT) ligand were observed in SH-SY5Y cells overexpressing parkin. The results were confirmed when parkin was transfected in HEK293 cells stably expressing DAT. In these cells, parkin enhanced the ubiquitination and degradation of DAT, increased its cell surface expression, and augmented dopamine uptake. The effects of parkin were significantly abrogated by its PD-causing mutations. Because the cell surface expression of functional DAT requires its oligomerization, misfolded DAT, induced either by the protein glycosylation inhibitor tunicamycin or by its C-terminal truncation, significantly attenuated cell surface expression of native DAT and reduced dopamine uptake. Expression of parkin, but not its T240R mutant, significantly alleviated these detrimental effects of misfolded DAT. Thus, our studies suggest that parkin increases dopamine uptake by enhancing the ubiquitination and degradation of misfolded DAT, so as to prevent it from interfering with the oligomerization and cell surface expression of native DAT. This function of parkin would enhance the precision of dopaminergic transmission, increase the efficiency of dopamine utilization, and reduce dopamine toxicity on neighboring cells.

Received for publication, August 13, 2004 , and in revised form, October 12, 2004.

^* This work is supported by National Institutes of Health Grant NS41722 (to J. F.) and Howard Hughes Medical Institute Biomedical Research Support Program Grant 53000261 (SUNY-Buffalo). 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 Physiology and Biophysics, State University of New York at Buffalo, 124 Sherman Hall, Buffalo, NY 14214. Tel.: 716-829-2345; Fax: 716-829-2699; E-mail: jianfeng{at}buffalo.edu.

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