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Molecular Pharmacology

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Research ArticleArticle

Desensitization and Trafficking of μ-Opioid Receptors in Locus Ceruleus Neurons: Modulation by Kinases

Seksiri Arttamangkul, Elaine K. Lau, Hsin-Wei Lu and John T. Williams
Molecular Pharmacology March 2012, 81 (3) 348-355; DOI: https://doi.org/10.1124/mol.111.076208
Seksiri Arttamangkul
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Elaine K. Lau
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Hsin-Wei Lu
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John T. Williams
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Abstract

The phosphorylation of μ-opioid receptors (MOPRs) by G protein-coupled receptor kinases (GRKs), followed by arrestin binding, is thought to be a key pathway leading to desensitization and internalization. The present study used the combination of intracellular and whole-cell recordings from rats and mice, as well as live cell imaging of Flag-tagged MOPRs from mouse locus ceruleus neurons, to examine the role of protein kinases in acute desensitization and receptor trafficking. Inhibition of GRKs by using heparin or GRK2-mutant mice did not block desensitization or alter the rate of recovery from desensitization. The nonselective kinase inhibitor staurosporine did not reduce the extent of [Met5]enkephalin (ME)-induced desensitization but increased the rate of recovery from desensitization. In the presence of staurosporine, ME-activated FlagMOPRs were internalized but did not traffic away from the plasma membrane. The increased rate of recovery from desensitization correlated with the enhancement in the recycling of receptors to the plasma membrane. ME-induced MOPR desensitization persisted and the trafficking of receptors was modified after inhibition of protein kinases. The results suggest that desensitization of MOPRs may be an early step after agonist binding that is modulated by but is not dependent on kinase activity.

Footnotes

  • This work was supported by National Institutes of Health National Institute of Drug Abuse [Grants DA08163, DA026617].

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

    http://dx.doi.org/10.1124/mol.111.076208.

  • ABBREVIATIONS:

    MOPR
    μ-opioid receptor
    NaPP1
    1-(1,1-dimethyethyl)-3-(1-napthalenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
    GPCR
    G protein-coupled receptor
    GRK
    G protein-coupled receptor kinase
    ME
    [Met5]enkephalin
    LC
    locus ceruleus
    ArrKO
    arrestin 3-knockout
    ACSF
    artificial cerebrospinal fluid
    FlagMOPR
    Flag-tagged μ-opioid receptor
    ANOVA
    analysis of variance
    BAPTA
    1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid
    MAPK
    mitogen-activated protein kinase
    DAMGO
    [d-Ala2,N-Me-Phe4,Gly5-ol]enkephalin
    AMPA
    α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
    (+)-MK801
    dizocilpine maleate
    SB203580
    4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole.

  • Received October 4, 2011.
  • Accepted November 23, 2011.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 81 (3)
Molecular Pharmacology
Vol. 81, Issue 3
1 Mar 2012
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Research ArticleArticle

Kinase Inhibition: MOPR Desensitization and Internalization

Seksiri Arttamangkul, Elaine K. Lau, Hsin-Wei Lu and John T. Williams
Molecular Pharmacology March 1, 2012, 81 (3) 348-355; DOI: https://doi.org/10.1124/mol.111.076208

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Research ArticleArticle

Kinase Inhibition: MOPR Desensitization and Internalization

Seksiri Arttamangkul, Elaine K. Lau, Hsin-Wei Lu and John T. Williams
Molecular Pharmacology March 1, 2012, 81 (3) 348-355; DOI: https://doi.org/10.1124/mol.111.076208
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