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Molecular Pharmacology

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Research ArticleArticle

μ-Opioid Receptors: Correlation of Agonist Efficacy for Signalling with Ability to Activate Internalization

Jamie McPherson, Guadalupe Rivero, Myma Baptist, Javier Llorente, Suleiman Al-Sabah, Cornelius Krasel, William L. Dewey, Chris P. Bailey, Elizabeth M. Rosethorne, Steven J. Charlton, Graeme Henderson and Eamonn Kelly
Molecular Pharmacology October 2010, 78 (4) 756-766; DOI: https://doi.org/10.1124/mol.110.066613
Jamie McPherson
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Guadalupe Rivero
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Myma Baptist
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Javier Llorente
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Suleiman Al-Sabah
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Cornelius Krasel
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William L. Dewey
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Chris P. Bailey
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Elizabeth M. Rosethorne
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Steven J. Charlton
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Graeme Henderson
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Eamonn Kelly
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Abstract

We have compared the ability of a number of μ-opioid receptor (MOPr) ligands to activate G proteins with their abilities to induce MOPr phosphorylation, to promote association of arrestin-3 and to cause MOPr internalization. For a model of G protein-coupled receptor (GPCR) activation where all agonists stabilize a single active conformation of the receptor, a close correlation between signaling outputs might be expected. Our results show that overall there is a very good correlation between efficacy for G protein activation and arrestin-3 recruitment, whereas a few agonists, in particular endomorphins 1 and 2, display apparent bias toward arrestin recruitment. The agonist-induced phosphorylation of MOPr at Ser375, considered a key step in MOPr regulation, and agonist-induced internalization of MOPr were each found to correlate well with arrestin-3 recruitment. These data indicate that for the majority of MOPr agonists the ability to induce receptor phosphorylation, arrestin-3 recruitment, and internalization can be predicted from their ability as agonists to activate G proteins. For the prototypic MOPr agonist morphine, its relatively weak ability to induce MOPr internalization can be explained by its low agonist efficacy.

Footnotes

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

  • This work was supported by the Medical Research Council UK [Grant G0600943]; the National Institutes of Health National Institute on Drug Abuse [Grant DA020836]; and the Biotechnology and Biochemical Sciences Research Council [Grant BB/D012902/1].

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

    doi:10.1124/mol.110.066613.

  • ABBREVIATIONS:

    MOPr
    μ opioid receptor
    DAMGO
    [d-Ala2,N-MePhe4,Gly-ol]-enkephalin
    GPCR
    G protein-coupled receptor
    HEK
    human embryonic kidney
    EA
    enzyme acceptor
    FRET
    fluorescence resonance energy transfer
    CFP
    enhanced cyan fluorescent protein
    YFP
    enhanced yellow fluorescent protein
    HBBS
    Hanks' buffered saline solution
    ELISA
    enzyme-linked immunosorbent assay
    M6G
    morphine-6-glucuronide
    GRK2
    G protein-coupled receptor kinase 2
    GIRK
    G protein-gated K+ channel
    GTPγS
    guanosine 5′-O-(3-thio)triphosphate.

  • Received May 26, 2010.
  • Accepted July 20, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 78 (4)
Molecular Pharmacology
Vol. 78, Issue 4
1 Oct 2010
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Research ArticleArticle

μ-Opioid Receptors: Correlation of Agonist Efficacy for Signalling with Ability to Activate Internalization

Jamie McPherson, Guadalupe Rivero, Myma Baptist, Javier Llorente, Suleiman Al-Sabah, Cornelius Krasel, William L. Dewey, Chris P. Bailey, Elizabeth M. Rosethorne, Steven J. Charlton, Graeme Henderson and Eamonn Kelly
Molecular Pharmacology October 1, 2010, 78 (4) 756-766; DOI: https://doi.org/10.1124/mol.110.066613

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Research ArticleArticle

μ-Opioid Receptors: Correlation of Agonist Efficacy for Signalling with Ability to Activate Internalization

Jamie McPherson, Guadalupe Rivero, Myma Baptist, Javier Llorente, Suleiman Al-Sabah, Cornelius Krasel, William L. Dewey, Chris P. Bailey, Elizabeth M. Rosethorne, Steven J. Charlton, Graeme Henderson and Eamonn Kelly
Molecular Pharmacology October 1, 2010, 78 (4) 756-766; DOI: https://doi.org/10.1124/mol.110.066613
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