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J. Biol. Chem., Vol. 282, Issue 30, 22239-22247, July 27, 2007

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Membrane Glycoprotein M6a Interacts with the µ-Opioid Receptor and Facilitates Receptor Endocytosis and Recycling^*

From the Department of Pharmacology and Toxicology, Otto von Guericke University, 39120 Magdeburg, Germany

Using a yeast two-hybrid screen, the neuronal membrane glycoprotein M6a, a member of the proteolipid protein family, was identified to be associated with the µ-opioid receptor (MOPr). Bioluminescence resonance energy transfer and co-immunoprecipitation experiments confirmed that M6a interacts agonist-independently with MOPr in human embryonic kidney 293 cells co-expressing MOPr and M6a. Co-expression of MOPr with M6a, but not with M6b or DM20, exists in many brain regions, further supporting a specific interaction between MOPr and M6a. After opioid treatment M6a co-internalizes and then co-recycles with MOPr to cell surface in transfected human embryonic kidney 293 cells. Moreover, the interaction of M6a and MOPr augments constitutive and agonist-dependent internalization as well as the recycling rate of µ-opioid receptors. On the other hand, overexpression of a M6a-negative mutant prevents µ-opioid receptor endocytosis, demonstrating an essential role of M6a in receptor internalization. In addition, we demonstrated the interaction of M6a with a number of other G protein-coupled receptors (GPCRs) such as the -opioid receptor, cannabinoid receptor CB1, and somatostatin receptor sst2A, suggesting that M6a might play a general role in the regulation of certain GPCRs. Taken together, these data provide evidence that M6a may act as a scaffolding molecule in the regulation of GPCR endocytosis and intracellular trafficking.

Received for publication, January 31, 2007 , and in revised form, May 18, 2007.

^* This work was supported by the SFB 426/A2 and the Graduate College 1167 of the Deutsche Forschungsgemeinschaft. 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.

¹ To whom correspondence should be addressed. Tel.: 49-391-6715372; Fax: 49-391-6715869; E-mail: thomas.koch{at}Medizin.Uni-Magdeburg.de.

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