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Originally published In Press as doi:10.1074/jbc.M301540200 on July 8, 2003

J. Biol. Chem., Vol. 278, Issue 38, 36848-36858, September 19, 2003
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The Intracellular Trafficking of Opioid Receptors Directed by Carboxyl Tail and a Di-leucine Motif in Neuro2A Cells*

Wei Wang, Horace H. Loh {ddagger} and Ping-Yee Law {ddagger} §

From the Department of Pharmacology, Medical School, University of Minnesota, Minneapolis, Minnesota 55455-0217

The µ- and {delta}-opioid receptors (MOR and DOR) differ significantly in their intracellular trafficking. MORs recycle back to the cell surface upon agonist treatment, whereas most internalized DORs are targeted to lysosomes for degradation. By exchanging the carboxyl tail domains of MOR and DOR and expressing the receptor chimeras in mouse neuroblastoma Neuro2A cells, it could be demonstrated that the carboxyl tail domain is not the sole determinant in directing the intracellular trafficking in these Neuro2A cells. Deletion of the dileucine motif (Leu245-Leu246) within the third intracellular loop of DOR or the mutation of Leu245 to Met slowed the lysosomal targeting of these {delta}-opioid receptors. Meanwhile the mutation of Met264 to Leu increased the rate of agonist-induced receptor internalization and the lysosomal targeting of the wild type and the {delta}-opioid receptor carboxyl tail chimera of the µ-opioid receptor. These studies suggest interplay between a di-leucine motif and the carboxyl tail in the lysosomal targeting of the receptor.


Received for publication, February 13, 2003 , and in revised form, June 3, 2003.

* This work was supported in parts by National Institutes of Health Grants DA07339 and DA11806. 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.

{ddagger} Recipient of National Institutes of Health Grant K05 DA70544.

§ Recipient of National Institutes of Health Grant K05 DA00513. To whom correspondence should be addressed: Dept. of Pharmacology, Medical School, University of Minnesota, 6-120 Jackson Hall, 321 Church St. S.E., Minneapolis, MN 55455-0217. Tel.: 612-626-6539; Fax: 612-625-8408; E-mail: lawxx001{at}umn.edu.


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