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Molecular Pharmacology

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Research ArticleArticle

The μ-Opioid Receptor Variant N190K Is Unresponsive to Peptide Agonists yet Can be Rescued by Small-Molecule Drugs

Jean-Philippe Fortin, Lei Ci, Jonathan Schroeder, Carmit Goldstein, Maria Claudia Montefusco, Inga Peter, Steven E. Reis, Gordon S. Huggins, Martin Beinborn and Alan S. Kopin
Molecular Pharmacology November 2010, 78 (5) 837-845; DOI: https://doi.org/10.1124/mol.110.064188
Jean-Philippe Fortin
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Lei Ci
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Jonathan Schroeder
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Carmit Goldstein
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Maria Claudia Montefusco
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Inga Peter
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Steven E. Reis
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Gordon S. Huggins
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Martin Beinborn
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Alan S. Kopin
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Abstract

The μ-opioid receptor (MOR) plays an important role in modulating analgesia, feeding behavior, and a range of autonomic functions. In the current study, we investigated the degree to which 13 naturally occurring missense mutations affect the pharmacological properties of the human MOR. After expression of each receptor in human embryonic kidney 293 cells, signaling (Gαi/o-mediated) induced by peptide agonists was assessed using luciferase reporter gene assays. Multiple mutants (S66F, S147C, R260H, R265C, R265H, and S268P) show a significant reduction in agonist potency. At the N190K variant, agonist-mediated signaling was essentially absent. Enzyme-linked immunosorbent assay, microscopic analysis, and radioligand binding assays revealed that this mutant shows markedly reduced cell-surface expression, whereas all other receptor variants were expressed at normal levels. Surface expression of the N190K variant could be increased by incubation with the alkaloid agonist buprenorphine or with either naltrexone or naloxone, structurally related MOR antagonists. We were surprised to find that both putative antagonists, despite being inactive at the wild-type MOR, triggered a concentration-dependent increase in N190K receptor-mediated signaling. In contrast, peptidic ligands failed to promote expression or rescue function of the N190K mutant. Subsequent analysis of the N190K variant in an ethnically diverse cohort identified this isoform in a subgroup of African Americans. Taken together, our studies reveal that the N190K mutation leads to severe functional alterations and, in parallel, changes the response to established MOR ligands. The extent to which this mutation results in physiological abnormalities or affects drug sensitivity in selected populations (e.g., those with chronic pain or addiction) remains to be investigated.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the Fonds de la Recherche en Santé du Québec; the Canadian Institutes of Health Research (Fellowship Awards to J.-P.F.); and the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01-DK072497].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.064188.

  • ABBREVIATIONS:

    MOR
    μ-opioid receptor
    GPCR
    G protein-coupled receptor
    DAMGO
    [d-Ala2,N-MePhe4,Gly-ol]-enkephalin
    β-CNA
    β-chlornaltrexamine
    CTAP
    H-d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2
    HA
    hemagglutinin
    HEK
    human embryonic kidney
    WT
    wild type
    PBS
    phosphate-buffered saline
    PCR
    polymerase chain reaction
    ELISA
    enzyme-linked immunosorbent assay
    NTX
    naltrexone
    HDL
    high-density lipoprotein.

  • Received February 15, 2010.
  • Accepted August 11, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 78 (5)
Molecular Pharmacology
Vol. 78, Issue 5
1 Nov 2010
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Research ArticleArticle

The μ-Opioid Receptor Variant N190K Is Unresponsive to Peptide Agonists yet Can be Rescued by Small-Molecule Drugs

Jean-Philippe Fortin, Lei Ci, Jonathan Schroeder, Carmit Goldstein, Maria Claudia Montefusco, Inga Peter, Steven E. Reis, Gordon S. Huggins, Martin Beinborn and Alan S. Kopin
Molecular Pharmacology November 1, 2010, 78 (5) 837-845; DOI: https://doi.org/10.1124/mol.110.064188

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Research ArticleArticle

The μ-Opioid Receptor Variant N190K Is Unresponsive to Peptide Agonists yet Can be Rescued by Small-Molecule Drugs

Jean-Philippe Fortin, Lei Ci, Jonathan Schroeder, Carmit Goldstein, Maria Claudia Montefusco, Inga Peter, Steven E. Reis, Gordon S. Huggins, Martin Beinborn and Alan S. Kopin
Molecular Pharmacology November 1, 2010, 78 (5) 837-845; DOI: https://doi.org/10.1124/mol.110.064188
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