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Research ArticleArticle

Synergistic Regulation of β2-Adrenergic Receptor Sequestration: Intracellular Complement of β-Adrenergic Receptor Kinase and β-Arrestin Determine Kinetics of Internalization

Luc Ménard, Stephen S. G. Ferguson, Jie Zhang, Fang-Tsyr Lin, Robert J. Lefkowitz, Marc G. Caron and Larry S. Barak
Molecular Pharmacology May 1997, 51 (5) 800-808; DOI: https://doi.org/10.1124/mol.51.5.800
Luc Ménard
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Stephen S. G. Ferguson
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Jie Zhang
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Fang-Tsyr Lin
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Robert J. Lefkowitz
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Marc G. Caron
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Larry S. Barak
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Abstract

Two of the common mechanisms regulating G protein-coupled receptor (GPCR) signal transduction are phosphorylation and sequestration (internalization). Agonist-mediated receptor phosphorylation by the β-adrenergic receptor kinase (βARK) facilitates subsequent interaction with an arrestin protein, resulting in receptor desensitization. Studies of the β2-adrenergic receptor (β2AR) receptor in human embryonic kidney (HEK) 293 cells indicate that βARK and arrestin proteins (β-arrestins) also regulate sequestration. Consistent with this notion, we show in HEK 293 cells that reduction in or removal of the ability of the β2AR to be phosphorylated by βARK or to interact normally with β-arrestin substantially reduces agonist-mediated sequestration. To evaluate βARK and β-arrestin regulation of β2AR sequestration, we examined the relationship between βARK and/or β-arrestin expression and β2AR sequestration in a variety of cultured cells, including HEK 293, COS 7, CHO, A431, and CHW. COS cells had both the lowest levels of endogenous β-arrestin expression and β2AR sequestration, whereas HEK 293 had the highest. Overexpression of β-arrestin, but not βARK, in COS cells increased the extent of wild-type β2AR sequestration to levels observed in HEK 293 cells. However, a βARK phosphorylation-impaired β2AR mutant (Y326A) required the simultaneous overexpression of both βARK and β-arrestin for this to occur. Among all cell lines, sequestration correlated best with the product of βARK and β-arrestin expression. Moreover, an agonist-mediated translocation of wild-type β2AR and endogenous β-arrestin 2 to endocytic vesicles prepared from CHO fibroblasts was observed. These data suggest not only that the complement of cellular βARK and arrestin proteins synergistically regulate β2AR sequestration but also that β-arrestins directly regulate β2AR trafficking as well as desensitization.

Footnotes

    • Received November 21, 1996.
    • Accepted February 12, 1997.
  • Send reprint requests to: Dr. Larry Barak, Box 3287, Department of Cell Biology, Duke University, Durham, NC 27710. E-mail:lbarak{at}cellbio.duke.edu

  • ↵1 Current affiliation: BioSignal Inc., Montreal, Quebec, Canada H3J IR4.

  • This work was supported in part by National Institutes of Health Grant NS19576, a Bristol Myers Squibb Unrestricted Grant Award (M.G.C.), a K-08 award HL03422 (L.S.B.), and a Michael Smith Postdoctoral Fellowship from the MRC Canada (S.S.G.F.).

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Molecular Pharmacology: 51 (5)
Molecular Pharmacology
Vol. 51, Issue 5
1 May 1997
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Research ArticleArticle

Synergistic Regulation of β2-Adrenergic Receptor Sequestration: Intracellular Complement of β-Adrenergic Receptor Kinase and β-Arrestin Determine Kinetics of Internalization

Luc Ménard, Stephen S. G. Ferguson, Jie Zhang, Fang-Tsyr Lin, Robert J. Lefkowitz, Marc G. Caron and Larry S. Barak
Molecular Pharmacology May 1, 1997, 51 (5) 800-808; DOI: https://doi.org/10.1124/mol.51.5.800

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Research ArticleArticle

Synergistic Regulation of β2-Adrenergic Receptor Sequestration: Intracellular Complement of β-Adrenergic Receptor Kinase and β-Arrestin Determine Kinetics of Internalization

Luc Ménard, Stephen S. G. Ferguson, Jie Zhang, Fang-Tsyr Lin, Robert J. Lefkowitz, Marc G. Caron and Larry S. Barak
Molecular Pharmacology May 1, 1997, 51 (5) 800-808; DOI: https://doi.org/10.1124/mol.51.5.800
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