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Originally published In Press as doi:10.1074/jbc.M006352200 on November 6, 2000

J. Biol. Chem., Vol. 276, Issue 5, 3130-3137, February 2, 2001
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A Single Nucleotide Polymorphic Mutation in the Human µ-Opioid Receptor Severely Impairs Receptor Signaling*

Katia Befort, Dominique Filliol, Fabien M. Décaillot, Claire Gavériaux-Ruff, Margret R. HoeheDagger , and Brigitte L. Kieffer§

From the Laboratoire des Récepteurs et Protéines Membranaires, UPR CNRS 9050, ESBS, Parc d'Innovation, 67400 Illkirch, France and Dagger  Genome Research Laboratory, Max-Delbrück-Center, Robert-Rössle-Strasse 10, D-13092 Berlin, Germany

Large scale sequencing of the human µ-opioid receptor (hMOR) gene has revealed polymorphic mutations that occur within the coding region. We have investigated whether the mutations N40D in the extracellular N-terminal region, N152D in the third transmembrane domain, and R265H and S268P in the third intracellular loop alter functional properties of the receptor expressed in mammalian cells. The N152D receptor was produced at low densities. Binding affinities of structurally diverse opioids (morphine, diprenorphine, DAMGO and CTOP) and the main endogenous opioid peptides (beta -endorphin, [Met]enkephalin, and dynorphin A) were not markedly changed in mutant receptors (<3-fold). Receptor signaling was strongly impaired in the S268P mutant, with a reduction of efficacy and potency of several agonists (DAMGO, beta -endorphin, and morphine) in two distinct functional assays. Signaling at N40D and R265H mutants was highly similar to wild type, and none of the mutations induced detectable constitutive activity. DAMGO-induced down-regulation of receptor-binding sites, following 20 h of treatment, was identical in wild-type and mutant receptors. Our data show that natural sequence variations in hMOR gene have little influence on ligand binding or receptor down-regulation but could otherwise modify receptor density and signaling. Importantly, the S268P mutation represents a loss-of-function mutation for the human µ-opioid receptor, which may have an incidence on opioid-regulated behaviors or drug addiction in vivo.

* This work was supported by the Association de la Recherche pour le Cancer and the Center National de la Recherche Scientifique.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence and reprint requests should be addressed: CNRS UPR 9050, ESBS, Parc d'Innovation, 67400 Illkirch, France. Tel.: 33 3 88 65 52 82; Fax: 33 3 88 65 52 98; E-mail: briki@esbs.u-strasbg.fr.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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