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Molecular Pharmacology

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Research ArticleArticle—The Many Facets of Opioid Receptor Phosphorylation

Agonist Binding and Desensitization of the μ-Opioid Receptor Is Modulated by Phosphorylation of the C-Terminal Tail Domain

William T. Birdsong, Seksiri Arttamangkul, James R. Bunzow and John T. Williams
Molecular Pharmacology October 2015, 88 (4) 816-824; DOI: https://doi.org/10.1124/mol.114.097527
William T. Birdsong
Vollum Institute, Oregon Health & Science University, Portland, Oregon
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Seksiri Arttamangkul
Vollum Institute, Oregon Health & Science University, Portland, Oregon
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James R. Bunzow
Vollum Institute, Oregon Health & Science University, Portland, Oregon
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John T. Williams
Vollum Institute, Oregon Health & Science University, Portland, Oregon
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Abstract

Sustained activation of G protein–coupled receptors can lead to a rapid decline in signaling through acute receptor desensitization. In the case of the μ-opioid receptor (MOPr), this desensitization may play a role in the development of analgesic tolerance. It is understood that phosphorylation of MOPr promotes association with β-arrestin proteins, which then facilitates desensitization and receptor internalization. Agonists that induce acute desensitization have been shown to induce a noncanonical high-affinity agonist binding state in MOPr, conferring a persistent memory of prior receptor activation. In the current study, live-cell confocal imaging was used to investigate the role of receptor phosphorylation in agonist binding to MOPr. A phosphorylation cluster in the C-terminal tail of MOPr was identified as a mediator of agonist-induced affinity changes in MOPr. This site is unique from the primary phosphorylation cluster responsible for β-arrestin binding and internalization. Electrophysiologic measurements of receptor function suggest that both phosphorylation clusters may play a parallel role during acute receptor desensitization. Desensitization was unaffected by alanine mutation of either phosphorylation cluster, but was largely eliminated when both clusters were mutated. Overall, this work suggests that there are multiple effects of MOPr phosphorylation that appear to regulate MOPr function: one affecting β-arrestin binding and a second affecting agonist binding.

Footnotes

    • Received December 19, 2014.
    • Accepted April 30, 2015.
  • This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grant R01-DA08163]; and the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant P30-NS061800].

  • dx.doi.org/10.1124/mol.114.097527.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 88 (4)
Molecular Pharmacology
Vol. 88, Issue 4
1 Oct 2015
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Research ArticleArticle—The Many Facets of Opioid Receptor Phosphorylation

μ-Opioid Receptor Agonist Binding and Desensitization

William T. Birdsong, Seksiri Arttamangkul, James R. Bunzow and John T. Williams
Molecular Pharmacology October 1, 2015, 88 (4) 816-824; DOI: https://doi.org/10.1124/mol.114.097527

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Research ArticleArticle—The Many Facets of Opioid Receptor Phosphorylation

μ-Opioid Receptor Agonist Binding and Desensitization

William T. Birdsong, Seksiri Arttamangkul, James R. Bunzow and John T. Williams
Molecular Pharmacology October 1, 2015, 88 (4) 816-824; DOI: https://doi.org/10.1124/mol.114.097527
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