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J. Biol. Chem., Vol. 278, Issue 51, 51630-51637, December 19, 2003

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Heterodimerization of Substance P and µ-Opioid Receptors Regulates Receptor Trafficking and Resensitization^*

Manuela Pfeiffer, Susanne Kirscht, Ralf Stumm, Thomas Koch, Daifei Wu, Magdalena Laugsch, Helmut Schröder, Volker Höllt, and Stefan Schulz

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

The µ-opioid receptor (MOR1) and the substance P receptor (NK1) coexist and functionally interact in nociceptive brain regions; however, a molecular basis for this interaction has not been established. Using coimmunoprecipitation and bioluminescence resonance energy transfer (BRET), we show that MOR1 and NK1 can form heterodimers in HEK 293 cells coexpressing the two receptors. Although NK1-MOR1 heterodimerization did not substantially change the ligand binding and signaling properties of these receptors, it dramatically altered their internalization and resensitization profile. Exposure of the NK1-MOR1 heterodimer to the MOR1-selective ligand [D-Ala²,Me-Phe⁴,Gly⁵-ol]enkephalin (DAMGO) promoted cross-phosphorylation and cointernalization of the NK1 receptor. Conversely, exposure of the NK1-MOR1 heterodimer to the NK1-selective ligand substance P (SP) promoted cross-phosphorylation and cointernalization of the MOR1 receptor. In cells expressing MOR1 alone, -arrestin directs the receptors to clathrin-coated pits, but does not internalize with the receptor. In cells expressing NK1 alone, -arrestin internalizes with the receptor into endosomes. Interestingly, in cells coexpressing MOR1 and NK1 both DAMGO and SP induced the recruitment of -arrestin to the plasma membrane and cointernalization of NK1-MOR1 heterodimers with -arrestin into the same endosomal compartment. Consequently, resensitization of MOR1-dependent receptor functions was severely delayed in coexpressing cells as compared with cells expressing MOR1 alone. Together, our findings indicate that MOR1 by virtue of its physical interaction with NK1 is sequestered via an endocytotic pathway with delayed recycling and resensitization kinetics.

Received for publication, July 3, 2003 , and in revised form, September 22, 2003.

^* This work was supported by Deutsche Forschungsgemeinschaft Grant SCHU 924/4-3 (to S. S.) and by Bundesministerium für Bildung und Forschung Grant NBL3 (to M. P.). 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.

Both authors contributed equally to this work.

To whom correspondence should be addressed: Dept. of Pharmacology and Toxicology, Otto-von-Guericke University, 39120 Magdeburg, Leipziger Strasse 44, Germany. Tel.: 49-391-671-5881; Fax: 49-391-671-5869; E-mail: Stefan.Schulz{at}Medizin.Uni-Magdeburg.de.

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