Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling.
By S. Ferguson. Pharmacological Reviews, 2001
1,968 citations recorded by the source corpus.
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 beta-arrestins, which not only uncouple receptors from heterotrimeric G proteins but also target many GPCRs for internalization in clathrin-coated vesicles. beta-Arrestin-dependent endocytosis of GPCRs involves the direct interaction of the carboxyl-terminal tail domain of beta-arrestins with both beta-adaptin and clathrin. The focus of this review is the current and evolving understanding of the contribution of GRKs, beta-arrestins, and endocytosis to GPCR-specific patterns of desensitization and resensitization. In addition to their role as GPCR-specific endocytic adaptor proteins, beta-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, beta-arrestin-dependent GPCR internalization is involved in the intracellular compartmentalization of these protein complexes.
Subfields: Cellular and Molecular Neuroscience, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/041c83cbb28d655ad32721cde23ea7305582dea1
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Citations in the corpus
- Cellular Regulation of RGS Proteins: Modulators and Integrators of G Protein Signaling (2002, background): “Taken together, these findings suggest that mechanisms for uncoupling RGS from G could proceed in conjunction with well defined classical mechanisms that desensitize receptor and G protein actions such as receptor phosphorylation and internalization (Ferguson, 2001).”
- International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors (2010, background): “Activation of GPCRs leads to changes in receptor sensitivity (desensitization, sensitization, internalization) and trafficking, leading to changes in ligand efficacy (Ferguson, 2001).”
- Global gene profiling in human endometrium during the window of implantation. (2002, background): “-arrestin, -adaptin, and clathrin (61), are up-regulated, supporting attenuated G protein-coupled receptor signaling in the implantation window.”
- Biological basket weaving: formation and function of clathrin-coated vesicles. (2001, background): “In this case, ligand binding leads to phosphorylation of the GPCR, which is then recognized by cytoplasmic proteins of the β-arrestin family (Ferguson 2001).”
- International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. (2001, neutral): “Exposure of any GPCR to agonists for shorter or longer times generally leads to the attenuation of the agonist response (for recent reviews, see Krupnick and Benovic, 1998; Lefkowitz, 1998; Pitcher et al., 1998; Ferguson, 2001).”