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Review ArticleReview

Evolving Concepts in G Protein-Coupled Receptor Endocytosis: The Role in Receptor Desensitization and Signaling

Stephen S. G. Ferguson
Pharmacological Reviews March 2001, 53 (1) 1-24;
Stephen S. G. Ferguson
The John P. Robarts Research Institute and Departments of Physiology, Pharmacology and Toxicology, and Medicine, University of Western Ontario, London, Ontario, Canada
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Abstract

G protein-coupled receptors (GPCRs) are seven transmembrane proteins that form the largest single family of integral membrane receptors. GPCRs transduce information provided by extracellular stimuli into intracellular second messengers via their coupling to heterotrimeric G proteins and the subsequent regulation of a diverse variety of effector systems. Agonist activation of GPCRs also initiates processes that are involved in the feedback desensitization of GPCR responsiveness, the internalization of GPCRs, and the coupling of GPCRs to heterotrimeric G protein-independent signal transduction pathways. GPCR desensitization occurs as a consequence of G protein uncoupling in response to phosphorylation by both second messenger-dependent protein kinases and G protein-coupled receptor kinases (GRKs). GRK-mediated receptor phosphorylation promotes the binding of β-arrestins, which not only uncouple receptors from heterotrimeric G proteins but also target many GPCRs for internalization in clathrin-coated vesicles. β-Arrestin-dependent endocytosis of GPCRs involves the direct interaction of the carboxyl-terminal tail domain of β-arrestins with both β-adaptin and clathrin. The focus of this review is the current and evolving understanding of the contribution of GRKs, β-arrestins, and endocytosis to GPCR-specific patterns of desensitization and resensitization. In addition to their role as GPCR-specific endocytic adaptor proteins, β-arrestins also serve as molecular scaffolds that foster the formation of alternative, heterotrimeric G protein-independent signal transduction complexes. Similar to what is observed for GPCR desensitization and resensitization, β-arrestin-dependent GPCR internalization is involved in the intracellular compartmentalization of these protein complexes.

Footnotes

  • ↵1 Address for correspondence: Stephen S. G. Ferguson, The John P. Robarts Research Institute, University of Western Ontario, 100 Perth Dr., P.O. Box 5015, London, Ontario, Canada N6A 5K8. E-mail: ferguson{at}rri.on.ca

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Pharmacological Reviews: 53 (1)
Pharmacological Reviews
Vol. 53, Issue 1
1 Mar 2001
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Review ArticleReview

Evolving Concepts in G Protein-Coupled Receptor Endocytosis: The Role in Receptor Desensitization and Signaling

Stephen S. G. Ferguson
Pharmacological Reviews March 1, 2001, 53 (1) 1-24;

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Review ArticleReview

Evolving Concepts in G Protein-Coupled Receptor Endocytosis: The Role in Receptor Desensitization and Signaling

Stephen S. G. Ferguson
Pharmacological Reviews March 1, 2001, 53 (1) 1-24;
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    • Abstract
    • I. Introduction
    • II. G Protein-Coupled Receptor Desensitization
    • III. G Protein-Coupled Receptor Internalization
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