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Research ArticleArticle—The Many Facets of Opioid Receptor Phosphorylation

Role of Phosphorylation Sites in Desensitization of µ-Opioid Receptor

Arsalan Yousuf, Elke Miess, Setareh Sianati, Yan-Ping Du, Stefan Schulz and MacDonald J. Christie
Molecular Pharmacology October 2015, 88 (4) 825-835; DOI: https://doi.org/10.1124/mol.115.098244
Arsalan Yousuf
Discipline of Pharmacology, University of Sydney, New South Wales, Sydney, Australia (A.Y., S.Si., Y.-P.D., M.J.C.); and Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany (E.M., S.Sc.)
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Elke Miess
Discipline of Pharmacology, University of Sydney, New South Wales, Sydney, Australia (A.Y., S.Si., Y.-P.D., M.J.C.); and Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany (E.M., S.Sc.)
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Setareh Sianati
Discipline of Pharmacology, University of Sydney, New South Wales, Sydney, Australia (A.Y., S.Si., Y.-P.D., M.J.C.); and Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany (E.M., S.Sc.)
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Yan-Ping Du
Discipline of Pharmacology, University of Sydney, New South Wales, Sydney, Australia (A.Y., S.Si., Y.-P.D., M.J.C.); and Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany (E.M., S.Sc.)
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Stefan Schulz
Discipline of Pharmacology, University of Sydney, New South Wales, Sydney, Australia (A.Y., S.Si., Y.-P.D., M.J.C.); and Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany (E.M., S.Sc.)
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MacDonald J. Christie
Discipline of Pharmacology, University of Sydney, New South Wales, Sydney, Australia (A.Y., S.Si., Y.-P.D., M.J.C.); and Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany (E.M., S.Sc.)
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Abstract

Phosphorylation of residues in the C-terminal tail of the µ-opioid receptor (MOPr) is thought to be a key step in desensitization and internalization. Phosphorylation of C-terminal S/T residues is required for internalization (Just et al., 2013), but its role in desensitization is unknown. This study examined the influence of C-terminal phosphorylation sites on rapid desensitization of MOPr. Wild-type MOPr, a 3S/T-A mutant (S363A, T370A, S375A) that maintains internalization, 6S/T-A (S363A, T370A, S375A, T376A, T379A, T383A) and 11S/T-A (all C-terminal S/T residues mutated) mutants not internalized by MOPr agonists were stably expressed in AtT20 cells. Perforated patch-clamp recordings of MOPr-mediated activation of G-protein–activated inwardly rectifying potassium channel (Kir3.X) (GIRK) conductance by submaximal concentrations of Met5-enkephalin (ME) and somatostatin (SST; coupling to native SST receptor [SSTR]) were used to examine desensitization induced by exposure to ME and morphine for 5 minutes at 37°C. The rates of ME- and morphine-induced desensitization did not correlate with phosphorylation using phosphorylation site-specific antibodies. ME-induced MOPr desensitization and resensitization did not differ from wild-type for 3S/T-A and 6S/T-A but was abolished in 11S/T-A. Morphine-induced desensitization was unaffected in all three mutants, as was heterologous desensitization of SSTR. Morphine-induced desensitization (but not ME) was reduced by protein kinase C inhibition in wild-type MOPr and abolished in the 11S/T-A mutant, as was heterologous desensitization. These findings establish that MOPr desensitization can occur independently of S/T phosphorylation and internalization; however, C-terminal phosphorylation is necessary for some forms of desensitization because mutation of all C-terminal sites (11S/T-A) abolishes desensitization induced by ME.

Footnotes

    • Received February 3, 2015.
    • Accepted May 12, 2015.
  • This work was supported by the National Health and Medical Research Council of Australia [Grants 1011979 and 511914].

  • dx.doi.org/10.1124/mol.115.098244.

  • 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

Phosphorylation and Desensitization of µ-Opioid Receptors

Arsalan Yousuf, Elke Miess, Setareh Sianati, Yan-Ping Du, Stefan Schulz and MacDonald J. Christie
Molecular Pharmacology October 1, 2015, 88 (4) 825-835; DOI: https://doi.org/10.1124/mol.115.098244

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Research ArticleArticle—The Many Facets of Opioid Receptor Phosphorylation

Phosphorylation and Desensitization of µ-Opioid Receptors

Arsalan Yousuf, Elke Miess, Setareh Sianati, Yan-Ping Du, Stefan Schulz and MacDonald J. Christie
Molecular Pharmacology October 1, 2015, 88 (4) 825-835; DOI: https://doi.org/10.1124/mol.115.098244
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