The DOI matches its Crossref record; 46 of the 46 references it cites were found in a registry or an index.
Molecular determinants underlying the formation of stable intracellular G protein-coupled receptor-β-arrestin complexes after receptor endocytosis
Open accessAbstract
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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“Additionally, (Vargas-Pinilla et al., 2015) identified a new phosphorylation site in the OTR of Callithrix at R149S, and the shortening of a Ser cluster in the OTR of Saguinus that is important for β-arrestin mediated desensitization and receptor recycling (Innamorati et al., 1998; Oakley et al., 2001; Vargas-Pinilla et al., 2015).”
From Neuropeptide diversity and the regulation of social behavior in New World primates (2016) · cites this paper as Oakley et al., 2001
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Cites
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Structural Basis for β-Arrestins in GPCR Trafficking
Yoo, S. M., Kang, D. S., & Benovic, J. (2017) · Springer eBooks · doi:10.1007/978-3-319-57553-7_4 · Cited by 1
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“Correspondingly, the addition of the less phosphorylated CCR5pp3 and CCR5pp4 with lower affinities towards arrestin2 (both K D ~ 200 µ M, Table S1) (Isaikina et al., 2023), resulted in a considerable, similar reduction of the formed arrestin2-AP2 b 2 complex (Figure 4F).”
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Novel interactions of the 5-HT₂ₐ and related receptors with intracellular signalling proteins
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Effects of Urotensin II on Excitation-Contraction Coupling in Hypertrophic Heart Failure
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Snyder, J. C., Rochelle, L. K., Barak, L. S., & Caron, M. G. (2014) · PLoS ONE · doi:10.1371/annotation/7f83735d-53d4-42f3-b3b2-b05dd5db059c
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A high-resolution analysis of arrestin2 interactions responsible for CCR5 endocytosis
Petrovic, I., Desai, S., Isaikina, P., Abiko, L. A., Spang, A., & Grzesiek, S. (2026) · eLife · doi:10.7554/elife.106839.4
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Flores-Espinoza, E., Hahn, H., & Thomsen, A. R. B. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.03.680346
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“The ability of ,B-arrestin 2 to remain associated with these receptors depends on the presence of a cluster of Ser and Thr residues in the carboxyl tail that may be phosphorylated and interact with arrestins (Oakley et al. 2001).”
Background
Metadata
- 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.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-06
- Volume
- 276
- Issue
- 22
- Pages
- 19452-19460
- ISSN
- 0021-9258 (ISSN-L)
- 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
- 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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