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Molecular Pharmacology

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Research ArticleArticle

Protein Kinase C-Mediated Phosphorylation of the μ-Opioid Receptor and Its Effects on Receptor Signaling

Bo Feng, Zhihua Li and Jia Bei Wang
Molecular Pharmacology April 2011, 79 (4) 768-775; DOI: https://doi.org/10.1124/mol.110.069096
Bo Feng
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Zhihua Li
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Jia Bei Wang
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Abstract

Phosphorylation of the μ opioid receptor (MOPr), mediated by several protein kinases, is a critical process in the regulation of MOPr signaling. Although G protein-coupled receptor kinases are known to play an essential role in the agonist-induced phosphorylation and desensitization of MOPr, evidence suggests that other protein kinases, especially protein kinase C (PKC), also participate in the regulation of MOPr signaling. In this study, we investigated the biochemical nature and downstream effects of PKC-mediated MOPr phosphorylation. We observed in vitro phosphorylation of the MOPr C terminus by purified PKC. Protein mass spectrometry and site-directed mutagenesis implicated Ser363 of MOPr as the primary substrate for PKC, and this was confirmed in Chinese hamster ovary cells stably expressing full-length MOPr using an antibody that specifically recognizes phosphorylated Ser363. Alanine mutation of Ser363 did not affect the affinity of MOPr-ligand binding and the efficiency of receptor G-protein coupling. However, the S363A mutation attenuated the desensitization of receptor G-protein coupling induced by phorbol 12-myristate. Our research thus has identified a specific PKC phosphorylation site in MOPr and demonstrated that PKC-mediated phosphorylation of MOPr induces receptor desensitization at the G protein coupling level.

Footnotes

  • This work was supported by the National Institutes of Health National Institutes of Drug Abuse [Grant DA11925].

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

    doi:10.1124/mol.110.069096.

  • ABBREVIATIONS:

    GPCR
    G protein-coupled receptor
    CHO
    Chinese hamster ovary
    CT
    carboxyl terminal
    DAMGO
    [d-Ala2-N-Me-Phe4,Gly5-ol]-enkephalin
    EGFP
    enhanced green fluorescence protein
    GRK
    G protein-coupled receptor kinase
    GST
    glutathione transferase
    MALDI-TOF-MS
    matrix-assisted laser desorption ionization-time of flight-mass spectrometry
    MOPr
    μ opioid receptor
    PMA
    phorbol 12-myristate 12-acetate
    PKC
    protein kinase C
    WGA
    wheat germ agglutinin
    WT
    wild type
    AC
    adenylate cyclase
    MS
    mass spectrometry
    PCR
    polymerase chain reaction
    PAGE
    polyacrylamide gel electrophoresis
    TBS-T
    Tris-buffered saline/Tween 20
    ANOVA
    analysis of variance
    DMSO
    dimethyl sulfoxide
    PBS
    phosphate-buffered saline
    [35S]GTPγS
    guanosine 5′-O-(3-[35S]thio)triphosphate.

  • Received October 4, 2010.
  • Accepted January 5, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (4)
Molecular Pharmacology
Vol. 79, Issue 4
1 Apr 2011
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Research ArticleArticle

Protein Kinase C-Mediated Phosphorylation of the μ-Opioid Receptor and Its Effects on Receptor Signaling

Bo Feng, Zhihua Li and Jia Bei Wang
Molecular Pharmacology April 1, 2011, 79 (4) 768-775; DOI: https://doi.org/10.1124/mol.110.069096

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Research ArticleArticle

Protein Kinase C-Mediated Phosphorylation of the μ-Opioid Receptor and Its Effects on Receptor Signaling

Bo Feng, Zhihua Li and Jia Bei Wang
Molecular Pharmacology April 1, 2011, 79 (4) 768-775; DOI: https://doi.org/10.1124/mol.110.069096
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