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Research ArticleArticle

Differentiation of Opioid Drug Effects by Hierarchical Multi-Site Phosphorylation

Sascha Just, Susann Illing, Michelle Trester-Zedlitz, Elaine K. Lau, Sarah J. Kotowski, Elke Miess, Anika Mann, Christian Doll, Jonathan C. Trinidad, Alma L. Burlingame, Mark von Zastrow and Stefan Schulz
Molecular Pharmacology March 2013, 83 (3) 633-639; DOI: https://doi.org/10.1124/mol.112.082875
Sascha Just
Institute of Pharmacology and Toxicology (S.J., S.I., E.M., A.M., C.D., S.S.), Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany; Departments of Psychiatry (M.T.-Z., E.K.L., S.J.K., M.v.Z.), Pharmaceutical Chemistry (J.C.T., A.L.B.), Chemistry (A.L.B.), and Cellular and Molecular Pharmacology (M.v.Z.), University of California, San Francisco, California
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Susann Illing
Institute of Pharmacology and Toxicology (S.J., S.I., E.M., A.M., C.D., S.S.), Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany; Departments of Psychiatry (M.T.-Z., E.K.L., S.J.K., M.v.Z.), Pharmaceutical Chemistry (J.C.T., A.L.B.), Chemistry (A.L.B.), and Cellular and Molecular Pharmacology (M.v.Z.), University of California, San Francisco, California
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Michelle Trester-Zedlitz
Institute of Pharmacology and Toxicology (S.J., S.I., E.M., A.M., C.D., S.S.), Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany; Departments of Psychiatry (M.T.-Z., E.K.L., S.J.K., M.v.Z.), Pharmaceutical Chemistry (J.C.T., A.L.B.), Chemistry (A.L.B.), and Cellular and Molecular Pharmacology (M.v.Z.), University of California, San Francisco, California
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Elaine K. Lau
Institute of Pharmacology and Toxicology (S.J., S.I., E.M., A.M., C.D., S.S.), Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany; Departments of Psychiatry (M.T.-Z., E.K.L., S.J.K., M.v.Z.), Pharmaceutical Chemistry (J.C.T., A.L.B.), Chemistry (A.L.B.), and Cellular and Molecular Pharmacology (M.v.Z.), University of California, San Francisco, California
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Sarah J. Kotowski
Institute of Pharmacology and Toxicology (S.J., S.I., E.M., A.M., C.D., S.S.), Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany; Departments of Psychiatry (M.T.-Z., E.K.L., S.J.K., M.v.Z.), Pharmaceutical Chemistry (J.C.T., A.L.B.), Chemistry (A.L.B.), and Cellular and Molecular Pharmacology (M.v.Z.), University of California, San Francisco, California
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Elke Miess
Institute of Pharmacology and Toxicology (S.J., S.I., E.M., A.M., C.D., S.S.), Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany; Departments of Psychiatry (M.T.-Z., E.K.L., S.J.K., M.v.Z.), Pharmaceutical Chemistry (J.C.T., A.L.B.), Chemistry (A.L.B.), and Cellular and Molecular Pharmacology (M.v.Z.), University of California, San Francisco, California
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Anika Mann
Institute of Pharmacology and Toxicology (S.J., S.I., E.M., A.M., C.D., S.S.), Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany; Departments of Psychiatry (M.T.-Z., E.K.L., S.J.K., M.v.Z.), Pharmaceutical Chemistry (J.C.T., A.L.B.), Chemistry (A.L.B.), and Cellular and Molecular Pharmacology (M.v.Z.), University of California, San Francisco, California
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Christian Doll
Institute of Pharmacology and Toxicology (S.J., S.I., E.M., A.M., C.D., S.S.), Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany; Departments of Psychiatry (M.T.-Z., E.K.L., S.J.K., M.v.Z.), Pharmaceutical Chemistry (J.C.T., A.L.B.), Chemistry (A.L.B.), and Cellular and Molecular Pharmacology (M.v.Z.), University of California, San Francisco, California
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Jonathan C. Trinidad
Institute of Pharmacology and Toxicology (S.J., S.I., E.M., A.M., C.D., S.S.), Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany; Departments of Psychiatry (M.T.-Z., E.K.L., S.J.K., M.v.Z.), Pharmaceutical Chemistry (J.C.T., A.L.B.), Chemistry (A.L.B.), and Cellular and Molecular Pharmacology (M.v.Z.), University of California, San Francisco, California
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Alma L. Burlingame
Institute of Pharmacology and Toxicology (S.J., S.I., E.M., A.M., C.D., S.S.), Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany; Departments of Psychiatry (M.T.-Z., E.K.L., S.J.K., M.v.Z.), Pharmaceutical Chemistry (J.C.T., A.L.B.), Chemistry (A.L.B.), and Cellular and Molecular Pharmacology (M.v.Z.), University of California, San Francisco, California
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Mark von Zastrow
Institute of Pharmacology and Toxicology (S.J., S.I., E.M., A.M., C.D., S.S.), Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany; Departments of Psychiatry (M.T.-Z., E.K.L., S.J.K., M.v.Z.), Pharmaceutical Chemistry (J.C.T., A.L.B.), Chemistry (A.L.B.), and Cellular and Molecular Pharmacology (M.v.Z.), University of California, San Francisco, California
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Stefan Schulz
Institute of Pharmacology and Toxicology (S.J., S.I., E.M., A.M., C.D., S.S.), Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany; Departments of Psychiatry (M.T.-Z., E.K.L., S.J.K., M.v.Z.), Pharmaceutical Chemistry (J.C.T., A.L.B.), Chemistry (A.L.B.), and Cellular and Molecular Pharmacology (M.v.Z.), University of California, San Francisco, California
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Abstract

Differences in the ability of opioid drugs to promote regulated endocytosis of μ-opioid receptors are related to their tendency to produce drug tolerance and dependence. Here we show that drug-specific differences in receptor internalization are determined by a conserved, 10-residue sequence in the receptor’s carboxyl-terminal cytoplasmic tail. Diverse opioids induce receptor phosphorylation at serine (S)375, present in the middle of this sequence, but opioids differ markedly in their ability to drive higher-order phosphorylation on flanking residues [threonine (T)370, T376, and T379]. Multi-phosphorylation is required for the endocytosis-promoting activity of this sequence and occurs both sequentially and hierarchically, with S375 representing the initiating site. Higher-order phosphorylation involving T370, T376, and T379 specifically requires GRK2/3 isoforms, and the same sequence controls opioid receptor internalization in neurons. These results reveal a biochemical mechanism differentiating the endocytic activity of opioid drugs.

Footnotes

  • This work was supported by the Deutsche Forschungsgemeinschaft [SCH924/11-2]; the National Institutes of Health National Institute on Drug Abuse [Grants DA010711 and DA012864]; and the National Institutes of Health National Center for Research Resources [Grant P41RR001614].

  • dx.doi.org/10.1124/mol.112.082875.

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

  • Received October 11, 2012.
  • Accepted December 13, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 83 (3)
Molecular Pharmacology
Vol. 83, Issue 3
1 Mar 2013
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Research ArticleArticle

Hierarchical Multi-Site Phosphorylation of Opioid Receptors

Sascha Just, Susann Illing, Michelle Trester-Zedlitz, Elaine K. Lau, Sarah J. Kotowski, Elke Miess, Anika Mann, Christian Doll, Jonathan C. Trinidad, Alma L. Burlingame, Mark von Zastrow and Stefan Schulz
Molecular Pharmacology March 1, 2013, 83 (3) 633-639; DOI: https://doi.org/10.1124/mol.112.082875

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Research ArticleArticle

Hierarchical Multi-Site Phosphorylation of Opioid Receptors

Sascha Just, Susann Illing, Michelle Trester-Zedlitz, Elaine K. Lau, Sarah J. Kotowski, Elke Miess, Anika Mann, Christian Doll, Jonathan C. Trinidad, Alma L. Burlingame, Mark von Zastrow and Stefan Schulz
Molecular Pharmacology March 1, 2013, 83 (3) 633-639; DOI: https://doi.org/10.1124/mol.112.082875
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