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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Background
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BackgroundInfluential
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Background
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Background
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Background
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Background
Ser352 and Ser354 in the carboxyl terminus of the human P2Y1 receptor are required for agonist‐promoted phosphorylation and internalization in MDCK cells
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Background
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“3) and are involved in the regulation of receptor desensitization, sequestration, and resensitization [6,11].”
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Background
CXCR2 Inverse Agonism Detected by Arrestin Redistribution
Kredel, S., Wolff, M., Wiedenmann, J., Moepps, B., Nienhaus, G. U., Gierschik, P., Kistler, B., & Heilker, R. (2009) · SLAS DISCOVERY · doi:10.1177/1087057109344616 · Cited by 6
Deubiquitinases and Their Emerging Roles in β-Arrestin-Mediated Signaling
Shenoy, S. K. (2014) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/b978-0-12-397925-4.00020-1 · Cited by 6
Canonical and Noncanonical Signaling Roles of β-Arrestins in Inflammation and Immunity
Ahmadzai, M. M., Broadbent, D. G., Occhiuto, C. J., Yang, C., Das, R., & Subramanian, H. (2017) · Advances in immunology · doi:10.1016/bs.ai.2017.05.004 · Cited by 6
Dissecting the structural features of β-arrestins as multifunctional proteins
Yun, Y., Ji, J., & Lee, H. H. (2021) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2021.140603 · Cited by 5
High Content Screening to Monitor G Protein-Coupled Receptor Internalisation
Heilker, R. (2007) · Ernst Schering Research Foundation workshop/Ernst Schering Foundation Symposium proceedings · doi:10.1007/2789_2006_011 · Cited by 6
“for the β2 adrenergic receptor, the ArrGFP is released after the formation of clathrin-coated pits ( Oakley et al. 2000, 2001 ).”
Background
A lipidated peptide derived from the C-terminal tail of the vasopressin 2 receptor shows promise as a new β-arrestin inhibitor
Brouillette, R. L., Mona, C. E., Desgagné, M., Hassanzedeh, M., Breault, É., Lussier, F., Belleville, K., Longpré, J., Grandbois, M., Boudreault, P., et al. (2025) · Pharmacological Research · doi:10.1016/j.phrs.2025.107597 · Cited by 5
Mécanismes moléculaires de la tolérance aux opiacés et aux cannabinoïdes
Marie, N. (2009) · Réanimation · doi:10.1016/j.reaurg.2009.06.016 · Cited by 5
Triphenylmethane Dye Activation of Beta-Arrestin
Barak, L. S., Bai, Y., Snyder, J. C., Wang, J., Chen, W., & Caron, M. G. (2013) · Biochemistry · doi:10.1021/bi400217r · Cited by 5
A Ser/Thr cluster within the C‐terminal domain of the rat prostaglandin receptor EP3α is essential for agonist‐induced phosphorylation, desensitization and internalization
Neuschäfer‐Rube, F., Hermosilla, R., Kuna, M., Pathe‐Neuschäfer‐Rube, A., Schülein, R., & Püschel, G. P. (2005) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0706282 · Cited by 5
“Clusters of Ser/Thr residues in the C- terminal domain of many GPCR were shown to be important determinants for receptor desensitization, acting as targets for agonist-induced receptor phosphorylation and/or as binding sites for the adaptor protein b-arrestin (Oakley et al., 2001).”
Background
The endosomal–lysosomal system
Maxfield, F. R., & Mukherjee, S. (2004) · Oxford University Press eBooks · doi:10.1093/acprof:oso/9780198508786.003.0001 · Cited by 6
Molecular mechanism of β-arrestin 2 interaction with phosphorylated intracellular loop 3 of dopamine receptor D2
Kim, K., Ji, J. S., Kim, H. R., Choi, Y., Lee, H. H., Inoue, A., & Chung, K. Y. (2025) · Communications Biology · doi:10.1038/s42003-025-08649-w · Cited by 5
ArreSTick motif controls β-arrestin-binding stability and extends phosphorylation-dependent β-arrestin interactions to non-receptor proteins
Tóth, A. D., Soltész‐Katona, E., Kis, K., Guti, V., Gilzer, S., Prokop, S., Boros, R., Misák, Á., Balla, A., Várnai, P., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114241 · Cited by 4
Desensitization and internalization mechanisms of the 5‐HT4 receptors
Mnie‐Filali, O., & Piñeyro, G. (2012) · Wiley Interdisciplinary Reviews Membrane Transport and Signalling · doi:10.1002/wmts.52 · Cited by 4
Effects of intermittent treatment with parathyroid hormone (PTH) on osteoblastic differentiation and mineralization of mouse induced pluripotent stem cells in a 3D culture model
Sato, M., Aoki, H., Nakamura, T., Onodera, S., Yamaguchi, A., Saitô, A., & Azuma, T. (2020) · Journal of Periodontal Research · doi:10.1111/jre.12762 · Cited by 4
Fluoroalkoxylated C-3 and C-9 (S)-12-bromostepholidine analogues with D1R antagonist activity
Namballa, H. K., Decker, A. M., Dorogan, M., Gudipally, A. R., Goclon, J., & Harding, W. W. (2023) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2023.106862 · Cited by 4
G Protein-Coupled Receptors
Thomsen, W. J., & Behan, D. P. (2007) · Elsevier eBooks · doi:10.1016/b0-08-045044-x/00062-6 · Cited by 4
Regulators of GPCR Activity
Luttrell, L. M. (2005) · Contemporary clinical neuroscience · doi:10.1007/978-1-59259-919-6_8 · Cited by 4
Single-molecule analysis of receptor-β-arrestin interactions in living cellsPreprint
Grimes, J., Kőszegi, Z., Lanoiselée, Y., Miljuš, T., O’Brien, S. L., Stępniewski, T. M., Medel-Lacruz, B., Baidya, M., Makarova, M., Owen, D. M., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.11.15.516577 · Cited by 4
“…complexes were widely assumed to be sufficiently stable to allow receptors and β-arrestins to reach CCPs together, as in the case of Class A GPCRs, or even co-internalize and remain associated in endosomes, as in the case of Class B receptors (Oakley et al., 1999, 2001; Oakley et al., 2000).”
Background
Structure-activity relationships of contulakin-G: Design, synthesis, and characterization of Thr10 analogs for pain modulation
Lanoie, A., Ferková, S., Caron-Duval, É., Dallagnol, J. C. C., Diarra, S., Murza, A., Tremblay, A., Théroux, L., Breault, É., Ranjbaran, A., et al. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2025.118664 · Cited by 3
Computational Modeling and Characterization of Peptides Derived from Nanobody Complementary-Determining Region 2 (CDR2) Targeting Active-State Conformation of the β2-Adrenergic Receptor (β2AR)
Senćanski, M., Glišić, S., Kubale, V., Cotman, M., Mavri, J., & Vrecl, M. (2024) · Biomolecules · doi:10.3390/biom14040423 · Cited by 3
Posttranslational Control of Protein Trafficking in the Post-Golgi Secretory and Endocytic Pathway
Piper, R. C., & Bryant, N. J. (2009) · Springer eBooks · doi:10.1007/978-0-387-93877-6_17 · Cited by 3
Inherited Disorders of Water Handling
Knoers, N. V. A. M., Levtchenko, E. N., & Bichet, D. G. (2022) · Springer eBooks · doi:10.1007/978-3-030-52719-8_112 · Cited by 3
Respiratory responses to intermittent hypoxia in unsedated piglets: relation to substance P binding in brainstem
Laferrière, A., & Moss, I. R. (2004) · Respiratory Physiology & Neurobiology · doi:10.1016/j.resp.2004.07.013 · Cited by 3
Arrestin-Dependent ERK Activation and Its Disruption
Luttrell, L. M., & Spiller, B. W. (2017) · Springer eBooks · doi:10.1007/978-3-319-57553-7_15 · Cited by 3
The repertoire of family A-peptide GPCRs in archaic hominins
Mata, X., Renaud, G., & Mollereau, C. (2019) · Peptides · doi:10.1016/j.peptides.2019.170154 · Cited by 3
Structural Diversity and Dynamics of Metabotropic Glutamate Receptor/Beta-Arrestin CouplingPreprint
Marx, D. C., Huynh, K. W., Gonzalez-Hernandez, A. J., Strauss, A., Rico, C. A., Siepe, D. H., Gallo, P. N., Lee, J., Moshtaghin, S. S., Arefin, A., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.02.03.636340 · Cited by 3
Membrane phosphoinositides allosterically tune β-arrestin dynamics to facilitate GPCR core engagementPreprint
Janetzko, J., Deutsch, J. C., Shi, Y., Siepe, D. H., Masureel, M., Liu, W., Viner, R., Inoue, A., Chu, S., Kobilka, B. K., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.06.06.658200 · Cited by 3
“However, given the range of measured phosphopeptide affinities, it is likely that most class A typology (weakly βarr-interacting) GPCRs 25,37,63,64 would lack suitable C-terminal phosphorylation to effectively capture βarr1 during brief, active-state fluctuations amid excursions to the plasma…”
Negative relationship between brain α1A-AR neurotransmission and βArr2 levels in anxious adolescent rats subjected to early life stress
Mahmoodkhani, M., Amini, M., Derafshpour, L., Ghasemi, M., & Mehranfard, N. (2020) · Experimental Brain Research · doi:10.1007/s00221-020-05937-1 · Cited by 2
Is oxytocin receptor signaling really dispensable for social attachment?
Danoff, J. S., Whelan, E. A., & Connelly, J. J. (2023) · Comprehensive Psychoneuroendocrinology · doi:10.1016/j.cpnec.2023.100178 · Cited by 2
“Ligand-bound OXTR can be internalized in a β-Arrestin dependent manner via interactions between the C terminus of OXTR and β-Arrestin [14].”
Background
GPCRs and β-arrestins — an on-off relationship
Thomsen, A. R. B. (2023) · Cell Research · doi:10.1038/s41422-023-00838-8 · Cited by 3
Near-Infrared Bioluminescence Assays for Protein–Protein Interactions and Cellular Membrane Fusion in Deep Tissues Using Split Akaluc Reconstitution
Li, Y., Kawamura, G., Dong, Q., Li, Q., & Ozawa, T. (2025) · Analytical Chemistry · doi:10.1021/acs.analchem.4c06986 · Cited by 2
Distinct Phosphorylation Patterns of AT1R by Biased Ligands and GRK Subtypes
Zhang, Z., Liu, C., Gong, J., Su, C., Liu, Z., Li, J., & Zhang, H. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26167988 · Cited by 2
“The phosphorylation pattern on the receptor’s tail influences β -arrestin binding and can induce distinct receptor conformations, thereby shaping downstream signaling outcomes [10–13].”
G-protein coupled receptors & autism -- reflections on a double-edged sword at the example of the oxytocin receptor system.
Walh, R. U. R. (2007) · PubMed · Cited by 2
Overview of Arrestin Mediated Signaling with Receptors and Non-receptor Binding Partners
Zhuo, Y., & Klug, C. S. (2017) · Springer eBooks · doi:10.1007/978-3-319-57553-7_2 · Cited by 2
Fusion of the β2‐adrenergic receptor with either Gαs or βarrestin‐2 produces constitutive signaling by each pathway and induces gain‐of‐function in BEAS‐2B cells
Garcia-Rojas, E. Y. L., Reyes‐Alcaraz, A., Ruan, K.-H., McConnell, B. K., & Bond, R. A. (2022) · FASEB BioAdvances · doi:10.1096/fba.2022-00038 · Cited by 1
EDITORIAL
Davenport, A. P., & Daly, C. J. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.00685.x · Cited by 2
Ligand-dependent internalization of Bombyx mori tachykinin-related peptide receptor is regulated by PKC, GRK5 and β-arrestin2/BmKurtz
He, X., Yan, L., Wu, Q., Zhang, G., & Zhou, N. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2020.118690 · Cited by 1
Arrestin-mediated trafficking and compartmentalized biology of GPCRs
Thomsen, A. R. B., Hahn, H., & Bunnett, N. W. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-85756-7.00004-2 · Cited by 1
Mécanismes d’action et rôles multiples des β-arrestines dans la biologie des récepteurs couplés aux protéines G
Reiter, É. (2021) · Biologie Aujourd hui · doi:10.1051/jbio/2021010 · Cited by 1
“Laprésenceoul ’ absencedeclustersdesérineet de thréonine dans l ’ extrémité C-terminale du RCPG conditionne l ’ af ﬁ nité du recrutement de la b -arrestine et affecte ainsi le tra ﬁ c intracellulaire d ’ un grand nombre de RCPG (Oakley et al. , 2000, 2001).”
Background
The clinical implication of β-arrestins-mediated signaling in memory and cognition
Aghdam, M. M., Mohebalizadeh, M., Sameei, P., & Majidinia, M. (2025) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-025-05323-x · Cited by 2
“Understanding the precise mechanisms and the structural basis of these interactions continues to be a critical area of research, providing insights into developing therapeutic agents targeting β-arrestin-biased pathways for various diseases [29–32].”
A neurotensin receptor type 1-derived pepducin acts as a biased allosteric modulator to regulate target receptor function
Brouillette, R. L., Lussier, F., Breault, É., Meneboo, N., Hassanzadeh, M., Tremblay, V., Chartier, M., Midavaine, É., Ulrich, L., Côté, J., et al. (2025) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2025.12.043 · Cited by 1
Factors modulating the assembly of human β2-adrenergic receptor–β-arrestin complexes
Wilhelm, F. M., Pluháčková, K., Janetzko, J., Masureel, M., Marsh, E., Hudspeth, J. D., Gassner, W., Schertler, G. F. X., Kobilka, B. K., & Müller, D. J. (2026) · Nature Structural & Molecular Biology · doi:10.1038/s41594-026-01842-3 · Cited by 1
“For class A GPCRs, such as the β 2 -adrenergic receptor (β 2 AR), which engage β-arrestins only transiently 4,39,40 , phosphoinositides, notably phosphatidylinositol 4,5-bisphosphate (PIP 2 ), are required for β-arrestin recruitment, desensitization and internalization 21,34 .”
Configurational diversity of metabotropic glutamate receptor complexes with beta-arrestins
Marx, D. C., Huynh, K., Gonzalez-Hernandez, A. J., Strauss, A., Rico, C., Siepe, D., Gallo, P. N., Lee, J., Moshtaghin, S. S., Arefin, A., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-77555-4 · Cited by 5
GPCRs and G Protein Activation
Waelbroeck, M. (2012) · InTech eBooks · doi:10.5772/33468 · Cited by 1
Role of β-Arrestins in Endosomal Sorting of G Protein-Coupled Receptors
Malik, R., & Marchese, A. (2012) · InTech eBooks · doi:10.5772/34739 · Cited by 1
“…of -Arrestins in Endosomal Sorting of G Protein-Coupled Receptors 257 Once -arrestins bind and desensitization and receptor internalization have initiated, the two proteins disassociate while the receptor internalizes onto endosomes (Oakley et al., 1999; Oakley et al., 2001; Oakley et al., 2000).”
BackgroundInfluential
How Arrestin Recognizes and Binds Active GPCRs
Sommer, M. E. (2017) · Springer eBooks · doi:10.1007/978-3-319-57553-7_8 · Cited by 1

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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