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Molecular Pharmacology

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Research ArticleArticle

Cholesterol Regulates μ-Opioid Receptor-Induced β-Arrestin 2 Translocation to Membrane Lipid Rafts

Yu Qiu, Yan Wang, Ping-Yee Law, Hong-Zhuan Chen and Horace H. Loh
Molecular Pharmacology July 2011, 80 (1) 210-218; DOI: https://doi.org/10.1124/mol.110.070870
Yu Qiu
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Yan Wang
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Ping-Yee Law
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Hong-Zhuan Chen
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Horace H. Loh
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Abstract

μ-Opioid receptor (OPRM1) is mainly localized in lipid raft microdomains but internalizes through clathrin-dependent pathways. Our previous studies demonstrated that disruption of lipid rafts by cholesterol-depletion reagent blocked the agonist-induced internalization of OPRM1 and G protein-dependent signaling. The present study demonstrated that reduction of cholesterol level decreased and culturing cells in excess cholesterol increased the agonist-induced internalization and desensitization of OPRM1, respectively. Further analyses indicated that modulation of cellular cholesterol level did not affect agonist-induced receptor phosphorylation but did affect membrane translocation of β-arrestins. The translocation of β-arrestins was blocked by cholesterol reduction, and the effect could be reversed by incubating with cholesterol. OptiPrep gradient separation of lipid rafts revealed that excess cholesterol retained more receptors in lipid raft domains and facilitated the recruitment of β-arrestins to these microdomains upon agonist activation. Moreover, excess cholesterol could evoke receptor internalization and protein kinase C-independent extracellular signal-regulated kinases activation upon morphine treatment. Therefore, these results suggest that cholesterol not only can influence OPRM1 localization in lipid rafts but also can effectively enhance the recruitment of β-arrestins and thereby affect the agonist-induced trafficking and agonist-dependent signaling of OPRM1.

Footnotes

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

  • This research was supported in parts by National Institutes of Health National Institute on Drug Abuse [Grants DA007339, DA016674, DA000564, DA011806, K05-DA00513] (the last to P.Y.L.); the National Great Basic Science Project of China [Grant 2010CB529806]; and Shanghai Natural Science foundation [Grant 10ZR1417000].

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

    doi:10.1124/mol.110.070870.

  • ABBREVIATIONS:

    OPRM1
    μ-opioid receptor
    MβCD
    methyl-β-cyclodextrin
    βArr
    β-arrestin
    HA
    hemagglutinin
    Ro-31-8425
    bisindolylmaleimide X
    GFP
    green fluorescent protein
    DAMGO
    [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin
    N2A
    neuro2A neuroblastoma cell
    PIPES
    piperazine-N,N′-bis(2-ethanesulfonic acid)
    ERK
    extracellular signal-regulated kinase
    TR
    transferrin receptor
    PKC
    protein kinase C.

  • Received December 30, 2010.
  • Accepted April 25, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (1)
Molecular Pharmacology
Vol. 80, Issue 1
1 Jul 2011
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Research ArticleArticle

Cholesterol Regulates μ-Opioid Receptor-Induced β-Arrestin 2 Translocation to Membrane Lipid Rafts

Yu Qiu, Yan Wang, Ping-Yee Law, Hong-Zhuan Chen and Horace H. Loh
Molecular Pharmacology July 1, 2011, 80 (1) 210-218; DOI: https://doi.org/10.1124/mol.110.070870

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Research ArticleArticle

Cholesterol Regulates μ-Opioid Receptor-Induced β-Arrestin 2 Translocation to Membrane Lipid Rafts

Yu Qiu, Yan Wang, Ping-Yee Law, Hong-Zhuan Chen and Horace H. Loh
Molecular Pharmacology July 1, 2011, 80 (1) 210-218; DOI: https://doi.org/10.1124/mol.110.070870
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