Cited by 456Receptor Mechanisms and SignalingCellular transport and secretionNeuropeptides and Animal Physiology

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Molecular determinants underlying the formation of stable intracellular G protein-coupled receptor-β-arrestin complexes after receptor endocytosis

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Oakley, Robert H., Laporte, Stéphane A., Holt, Jason A., Barak, Larry S., Caron, Marc G.·2001·Journal of Biological Chemistry

DOI 10.1074/jbc.m101450200

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Abstract

beta-Arrestins bind agonist-activated G protein-coupled receptors (GPCRs) and mediate their desensitization and internalization. Although beta-arrestins dissociate from some receptors at the plasma membrane, such as the beta2 adrenergic receptor, they remain associated with other GPCRs and internalize with them into endocytic vesicles. Formation of stable receptor-beta-arrestin complexes that persist inside the cell impedes receptor resensitization, and the aberrant formation of these complexes may play a role in GPCR-based diseases (Barak, L. S., Oakley, R. H., Laporte, S. A., and Caron, M. G. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 93-98). Here, we investigate the molecular determinants responsible for sustained receptor/beta-arrestin interactions. We show in real time and in live human embryonic kidney (HEK-293) cells that a beta-arrestin-2-green fluorescent protein conjugate internalizes into endocytic vesicles with agonist-activated neurotensin-1 receptor, oxytocin receptor, angiotensin II type 1A receptor, and substance P receptor. Using receptor mutagenesis, we demonstrate that the ability of beta-arrestin to remain associated with these receptors is mediated by specific clusters of serine and threonine residues located in the receptor carboxyl-terminal tail. These clusters are remarkably conserved in their position within the carboxyl-terminal domain and serve as primary sites of agonist-dependent receptor phosphorylation. In addition, we identify a beta-arrestin mutant with enhanced affinity for the agonist-activated beta2-adrenergic receptor that traffics into endocytic vesicles with receptors that lack serine/threonine clusters and normally dissociate from wild-type beta-arrestin at the plasma membrane. By identifying receptor and beta-arrestin residues critical for the formation of stable receptor-beta-arrestin complexes, these studies provide novel targets for regulating GPCR responsiveness and treating diseases resulting from abnormal GPCR/beta-arrestin interactions.

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Authors: Oakley, R. H., Laporte, S. A., Holt, J. A., Barak, L. S., & Caron, M. G.
Affiliations: Howard Hughes Medical Institute (US)
Corresponding author: Caron, Marc G.
ORCID: Oakley, Robert H.
Laporte, Stéphane A.
Barak, Larry S.
Caron, Marc G.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2001-06
Volume: 276
Issue: 22
Pages: 19452-19460
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m101450200
OpenAlex: W2083334427
Cited by: 455
References: 45
Citations by year: 2026: 7 · 2025: 19 · 2024: 8 · 2023: 15 · 2022: 14 · 2021: 13 · 2020: 16 · 2019: 10 · 2018: 11 · 2017: 23 · 2016: 9 · 2015: 9 · 2014: 18 · 2013: 17 · 2012: 19
FWCI: 10.61
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 7062 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: National Institutes of Health (5r01hl061365-04)
National Heart, Lung, and Blood Institute (HL61365)
National Institute of Neurological Disorders and Stroke (NS-19576, R01NS019576)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords: beta-arrestin, G protein-coupled receptors, receptor internalization, receptor desensitization, receptor resensitization, serine/threonine phosphorylation, carboxyl-terminal tail, beta2-adrenergic receptor, oxytocin receptor, angiotensin II type 1a receptor, neurokinin-1 receptor, endocytic vesicles
MeSH terms: beta-Arrestins, beta-Arrestin 2, Amino Acid Sequence, Cell Line, Cell Membrane, Endocytosis, Humans, Luminescent Proteins, Microscopy, Fluorescence, Molecular Sequence Data, Mutation, Phosphorylation, Plasmids, Protein Binding, Receptors, Angiotensin, Receptors, Cell Surface, Recombinant Fusion Proteins, Time Factors, Transfection, Mutagenesis, Site-Directed, Sequence Homology, Amino Acid, Protein Structure, Tertiary, Receptors, Neurotensin, Receptors, Neurokinin-1, Receptors, Oxytocin, Microscopy, Confocal, Arrestins, Receptor, Angiotensin, Type 1, Green Fluorescent Proteins

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Molecular determinants underlying the formation of stable intracellular G protein-coupled receptor-β-arrestin complexes after receptor endocytosis

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