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J. Biol. Chem., Vol. 278, Issue 38, 36733-36739, September 19, 2003

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µ-Opioid Receptor Desensitization

ROLE OF RECEPTOR PHOSPHORYLATION, INTERNALIZATION, AND RESENSITIZATION^*

Yu Qiu , Ping-Yee Law and Horace H. Loh

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

It is generally accepted that the internalization and desensitization of µ-opioid receptor (MOR) involves receptor phosphorylation and -arrestin recruitment. However, a mutant MOR, which is truncated after the amino acid residue Ser³⁶³ (MOR363D), was found to undergo phosphorylation-independent internalization and desensitization. As expected, MOR363D, missing the putative agonist-induced phosphorylation sites, did not exhibit detectable agonist-induced phosphorylation. MOR363D underwent slower internalization as reflected in the attenuation of membrane translocation of -arrestin 2 when compared with wild type MOR, but the level of receptor being internalized was similar to that of wild type MOR after 4 h of etorphine treatment. Furthermore, MOR363D was observed to desensitize faster than that of wild type MOR upon agonist activation. Surface biotinylation assay demonstrated that the wild type receptors recycled back to membrane after agonist-induced internalization, which contributed to the receptor resensitization and thus partially reversed the receptor desensitization. On the contrary, MOR363D did not recycle after internalization. Hence, MOR desensitization is controlled by the receptor internalization and the recycling of internalized receptor to cell surface in an active state. Taken together, our data indicated that receptor phosphorylation is not absolutely required in the internalization, but receptor phosphorylation and subsequent -arrestin recruitment play important roles in the resensitization of internalized receptors.

Received for publication, June 4, 2003 , and in revised form, July 11, 2003.

^* This research is supported in part by National Institutes of Health Grants DA0564, DA11806, and DA07339 and Grants K05 DA70544 (to H. H. L.) and K05 DA00513 (to P. Y. L.) from the Alice and Frederick Stark Fund of Minnesota Medical Foundation. 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 Pharmacology, Medical School, University of Minnesota, 6-120 Jackson Hall, 321 Church St. S.E., Minneapolis, MN 55455. Tel.: 612-626-6539; Fax: 612-625-8408; E-mail: qiuxx014{at}umn.edu.

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