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Review ArticleReview Article

Beyond Desensitization: Physiological Relevance of Arrestin-Dependent Signaling

Louis M. Luttrell and Diane Gesty-Palmer
David R. Sibley, ASSOCIATE EDITOR
Pharmacological Reviews June 2010, 62 (2) 305-330; DOI: https://doi.org/10.1124/pr.109.002436
Louis M. Luttrell
Departments of Medicine and Biochemistry & Molecular Biology, Medical University of South Carolina (L.M.L.) and the Ralph H. Johnson Veterans Affairs Medical Center (L.M.L.), Charleston, South Carolina; and Department of Medicine, Duke University Medical Center (D.G.-P.) and the Durham Veterans Affairs Medical Center (D.G.-P.), Durham, North Carolina
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Diane Gesty-Palmer
Departments of Medicine and Biochemistry & Molecular Biology, Medical University of South Carolina (L.M.L.) and the Ralph H. Johnson Veterans Affairs Medical Center (L.M.L.), Charleston, South Carolina; and Department of Medicine, Duke University Medical Center (D.G.-P.) and the Durham Veterans Affairs Medical Center (D.G.-P.), Durham, North Carolina
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David R. Sibley
Departments of Medicine and Biochemistry & Molecular Biology, Medical University of South Carolina (L.M.L.) and the Ralph H. Johnson Veterans Affairs Medical Center (L.M.L.), Charleston, South Carolina; and Department of Medicine, Duke University Medical Center (D.G.-P.) and the Durham Veterans Affairs Medical Center (D.G.-P.), Durham, North Carolina
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This article has a correction. Please see:

  • Correction to “Beyond Desensitization: Physiological Relevance of Arrestin-Dependent Signaling” - September 01, 2010

Abstract

Heptahelical G protein-coupled receptors are the most diverse and therapeutically important family of receptors in the human genome. Ligand binding activates heterotrimeric G proteins that transmit intracellular signals by regulating effector enzymes or ion channels. G protein signaling is terminated, in large part, by arrestin binding, which uncouples the receptor and G protein and targets the receptor for internalization. It is clear, however, that heptahelical receptor signaling does not end with desensitization. Arrestins bind a host of catalytically active proteins and serve as ligand-regulated scaffolds that recruit protein and lipid kinase, phosphatase, phosphodiesterase, and ubiquitin ligase activity into the receptor-arrestin complex. Although many of these arrestin-bound effectors serve to modulate G protein signaling, degrading second messengers and regulating endocytosis and trafficking, other signals seem to extend beyond the receptor-arrestin complex to regulate such processes as protein translation and gene transcription. Although these findings have led to a re-envisioning of heptahelical receptor signaling, little is known about the physiological roles of arrestin-dependent signaling. In vivo, the duality of arrestin function makes it difficult to dissociate the consequences of arrestin-dependent desensitization from those that might be ascribed to arrestin-mediated signaling. Nonetheless, recent evidence generated using arrestin knockouts, G protein-uncoupled receptor mutants, and arrestin pathway-selective “biased agonists” is beginning to reveal that arrestin signaling plays important roles in the retina, central nervous system, cardiovascular system, bone remodeling, immune system, and cancer. Understanding the signaling roles of arrestins may foster the development of pathway-selective drugs that exploit these pathways for therapeutic benefit.

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  • This article is available online at http://pharmrev.aspetjournals.org.

    doi:10.1124/pr.109.002436.

  • U.S. Government work not protected by U.S. copyright
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Pharmacological Reviews: 62 (2)
Pharmacological Reviews
Vol. 62, Issue 2
1 Jun 2010
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Review ArticleReview Article

Beyond Desensitization: Physiological Relevance of Arrestin-Dependent Signaling

Louis M. Luttrell and Diane Gesty-Palmer
Pharmacological Reviews June 1, 2010, 62 (2) 305-330; DOI: https://doi.org/10.1124/pr.109.002436

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Review ArticleReview Article

Beyond Desensitization: Physiological Relevance of Arrestin-Dependent Signaling

Louis M. Luttrell and Diane Gesty-Palmer
Pharmacological Reviews June 1, 2010, 62 (2) 305-330; DOI: https://doi.org/10.1124/pr.109.002436
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  • Article
    • Abstract
    • I. Introduction
    • II. The Duality of Arrestin Function
    • III. Arrestin Signaling in Vitro
    • IV. Dissociating Arrestin Signaling from Desensitization in Vivo
    • V. Arrestin Signaling in Vivo
    • VI. Summary and Future Directions
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