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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BackgroundResult
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Bimolecular fluorescence complementation: lighting up seven transmembrane domain receptor signalling networks
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“Irreversibility can also become an important consideration because some ligands and 7TM receptors (such as the b2-adrenoceptor) recruit b-arrestin transiently, while others form stable receptor-b-arrestin complexes which persist in endosomes (Oakley et al., 2001).”
Background
Role of beta-arrestin 2 downstream of dopamine receptors in the basal ganglia
Del’Guidice, T. (2011) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2011.00058 · Cited by 53
G Protein-Coupled Receptor Kinase 2 (GRK2) and 5 (GRK5) Exhibit Selective Phosphorylation of the Neurotensin Receptor in Vitro
Inagaki, S., Ghirlando, R., Vishnivetskiy, S. A., Homan, K. T., White, J. F., Tesmer, J. J. G., Gurevich, V. V., & Grisshammer, R. (2015) · Biochemistry · doi:10.1021/acs.biochem.5b00285 · Cited by 47
Phosphorylation of the δ-Opioid Receptor Regulates Its β-Arrestins Selectivity and Subsequent Receptor Internalization and Adenylyl Cyclase Desensitization
Qiu, Y. L., Loh, H. H., & Law, P. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m611258200 · Cited by 49
Parathyroid Hormone Receptor Recycling: Role of Receptor Dephosphorylation and β-Arrestin
Chauvin, S., Bencsik, M., Bambino, T., & Nissenson, R. A. (2002) · Molecular Endocrinology · doi:10.1210/me.2002-0049 · Cited by 49
Differential requirements for clathrin endocytic pathway components in cellular entry by Ebola and Marburg glycoprotein pseudovirions
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“By contrast, ARRB1, which is selectively important for MARVGP-mediated infection, recognizes phosphorylated serine and threonine residues onGPCRs (Oakley et al., 2001) andbinds both to the beta-adaptin subunit of AP-2 as well as directly to clathrin through its C-terminus (Traub, 2003;Traub, 2009).”
Background
Engagement of β-arrestin by transactivated insulin-like growth factor receptor is needed for V2 vasopressin receptor-stimulated ERK1/2 activation
Oligny-Longpré, G., Corbani, M., Zhou, J., Hogue, M., Guillon, G., & Bouvier, M. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1112422109 · Cited by 47
“To confirm that the recruitment of β-arrestins to IGFR and not V2R is responsible for the V2R-mediated ERK1/2 activation, we took advantage of a mutant form of V2R [V2R (Ala6)] in which phosphate acceptor residues that stabilize the receptor’s interaction with β-arrestins were replaced by alanines (37), thus decreasin…”
Background
Human substance P receptor lacking the C‐terminal domain remains competent to desensitize and internalize
Richardson, M. D., Balius, A. M., Yamaguchi, K., Freilich, E. R., Barak, L. S., & Kwatra, M. M. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.01577.x · Cited by 47
The third intracellular loop and carboxyl tail of neurokinin 1 and 3 receptors determine interactions with β-arrestins
Schmidlin, F., Roosterman, D., & Bunnett, N. W. (2003) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00541.2002 · Cited by 47
N-Formyl Peptide Receptor Phosphorylation Domains Differentially Regulate Arrestin and Agonist Affinity
Key, T. A., Foutz, T. D., Gurevich, V. V., Sklar, L. A., & Prossnitz, E. R. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m204687200 · Cited by 47
Biased Signaling and Allosteric Modulation at the FSHR
Landomiel, F., Pascali, F. D., Raynaud, P., Jean‐Alphonse, F., Yvinec, R., Pellissier, L. P., Bozon, V., Bruneau, G., Crépieux, P., Anne Poupon, B., et al. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00148 · Cited by 46
Ligand-specific receptor states: Implications for opiate receptor signalling and regulation
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Temporal Profiling of Orexin Receptor-Arrestin-Ubiquitin Complexes Reveals Differences between Receptor Subtypes
Dalrymple, M. B., Jaeger, W. C., Eidne, K. A., & Pfleger, K. D. G. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.223537 · Cited by 45
ML314: A Biased Neurotensin Receptor Ligand for Methamphetamine Abuse
Barak, L. S., Bai, Y., Peterson, S. M., Evron, T., Urs, N. M., Peddibhotla, S., Hedrick, M. P., Hershberger, P., Maloney, P., Chung, T. D. Y., et al. (2016) · ACS Chemical Biology · doi:10.1021/acschembio.6b00291 · Cited by 44
β-arrestin signalling and bias in hormone-responsive GPCRs
Reiter, É., Ayoub, M. A., Pellissier, L. P., Landomiel, F., Musnier, A., Trefier, A., Gandía, J., Pascali, F. D., Tahir, S., Yvinec, R., et al. (2017) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.01.052 · Cited by 45
“…S/T in C-term Gi1/Gi3 bias; β-arr bias; Gq bias (Azzi et al., 2003,Busnelli et al., 2012,Busnelli et al., 2013,Di Benedetto et al., 2014,Hasbi et al., 2004,Oakley et al., 2001,Passoni et al., 2016,Terrillon and Bar-Sagi, 2008) Adrenaline, epinephrine α1AR, α2AR, β1AR, β2AR, β3AR Microscopy,…”
Signaling at the endosome: cryo‐EM structure of a GPCR–G protein–beta‐arrestin megacomplex
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The Glucagon-like Peptide-2 Receptor C Terminus Modulates β-Arrestin-2 Association but Is Dispensable for Ligand-induced Desensitization, Endocytosis, and G-protein-dependent Effector Activation
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Arrestins
Walther, C., & Ferguson, S. S. G. (2013) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-394440-5.00004-8 · Cited by 44
Differential β-arrestin2 requirements for constitutive and agonist-induced internalization of the CB1 cannabinoid receptor
Gyombolai, P., Boros, E., Hunyady, L., & Turu, G. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.03.013 · Cited by 43
“Our findings demonstrating a class A pattern for CB1R are in good agreement with this theory, as the C-terminus of CB1R contains only one such cluster (463-SVSTDTS-469) (Oakley et al., 2001).”
BackgroundResultInfluential
Modulation of methuselah expression targeted to D rosophila insulin‐producing cells extends life and enhances oxidative stress resistance
Gimenez, L. E., Ghildyal, P., Fischer, K. E., Hu, H., Ja, W. W., Eaton, B. A., Wu, Y., Austad, S. N., & Ranjan, R. (2012) · Aging Cell · doi:10.1111/acel.12027 · Cited by 42
“Furthermore, b-arrestin is known to have a high affinity for secretin family GPCRs like MTH (Oakley et al., 2001).”
Background
β-Arrestin mediates oxytocin receptor signaling, which regulates uterine contractility and cellular migration
Grotegut, C. A., Feng, L., Mao, L., Heine, R. P., Murtha, A. P., & Rockman, H. A. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00390.2010 · Cited by 43
“Mutations of the OXTR in this highly conserved region of serine clusters within the carboxyl-terminal domain lead to unstable OXTR-arrestin interactions and failure of receptor internalization following agonist stimulation (33).”
BackgroundResultInfluential
Post‐endocytic fates of δ‐opioid receptor are regulated by GRK2‐mediated receptor phosphorylation and distinct β‐arrestin isoforms
Zhang, X., Wang, F., Chen, X., Chen, Y., & Ma, L. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05431.x · Cited by 43
Biased Signaling of the Angiotensin II Type 1 Receptor Can Be Mediated through Distinct Mechanisms
Bonde, M. M., Hansen, J. T., Sanni, S. J., Haunsø, S., Gammeltoft, S., Lyngsø, C., & Hansen, J. L. (2010) · PLoS ONE · doi:10.1371/journal.pone.0014135 · Cited by 41
“Truncation or mutation of serine or threonine residues in the C-terminal tail has been shown to disrupt this stable interaction with b-arrestin leading to increased signaling through G protein-dependent pathways [24,25,26,27,28,29].”
Background
Arresting angiotensin type 1 receptors
Thomas, W. G., & QIAN, H. (2003) · Trends in Endocrinology and Metabolism · doi:10.1016/s1043-2760(03)00023-7 · Cited by 43
β-Arrestin-2 BRET Biosensors Detect Different β-Arrestin-2 Conformations in Interaction with GPCRs
Oishi, A., Dam, J., & Jockers, R. (2019) · ACS Sensors · doi:10.1021/acssensors.9b01414 · Cited by 43
Exploring GPCR‐arrestin interfaces with genetically encoded crosslinkers
Böttke, T., Ernicke, S., Serfling, R., Ihling, C. H., Burda, E., Gurevich, V. V., Sinz, A., & Coin, I. (2020) · EMBO Reports · doi:10.15252/embr.202050437 · Cited by 45
“Other receptors forming stable complexes with arrestin include the angiotensin II type 1 receptor (AT 1 R), the oxytocin receptor, the neuro-tensin 1 receptor (NTS 1 R), and the secretin-like parathyroid hormone receptor (PTH1R) (Oakley et al , 2001; Vilardaga et al , 2002).”
The association of arrestin-3 with the follitropin receptor depends on receptor activation and phosphorylation
Krishnamurthy, H., Galet, C., & Ascoli, M. (2003) · Molecular and Cellular Endocrinology · doi:10.1016/s0303-7207(03)00088-1 · Cited by 42
Oxytocin in the Male Reproductive Tract; The Therapeutic Potential of Oxytocin-Agonists and-Antagonists
Stadler, B., Whittaker, M. R., Exintaris, B., & Middendorff, R. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.565731 · Cited by 43
Regulation of Oxytocin Receptor Responsiveness by G Protein-Coupled Receptor Kinase 6 in Human Myometrial Smooth Muscle
Willets, J. M., Brighton, P. J., Mistry, R., Morris, G. E., Konje, J. C., & Challiss, R. A. J. (2009) · Molecular Endocrinology · doi:10.1210/me.2009-0047 · Cited by 41
Amphioxus (Branchiostoma floridae) has orthologs of vertebrate odorant receptors
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“floridae ORs should be confirmed experimentally, however, the presence of several clusters of serine and threonine residues in the C termini suggests they may be sites for receptor phosphorylation as seen in other GPCRs [34,35].”
Background
Fluorescence correlation spectroscopy, combined with bimolecular fluorescence complementation, reveals the effects of β-arrestin complexes and endocytic targeting on the membrane mobility of neuropeptide Y receptors
Kilpatrick, L. E., Briddon, S. J., & Holliday, N. D. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2012.03.002 · Cited by 40
β-Arrestins: Multitask Scaffolds Orchestrating the Where and When in Cell Signalling
Laporte, S. A., & Scott, M. G. H. (2019) · Methods in molecular biology · doi:10.1007/978-1-4939-9158-7_2 · Cited by 41
Membrane-Proximal Region of the Carboxyl Terminus of the Gonadotropin-Releasing Hormone Receptor (GnRHR) Confers Differential Signal Transduction between Mammalian and Nonmammalian GnRHRs
Oh, D. Y., Song, J. A., Moon, J. S., Moon, M. J., Kim, J. I., Kim, K., Kwon, H. B., & Seong, J. Y. (2004) · Molecular Endocrinology · doi:10.1210/me.2004-0220 · Cited by 40
“The SFR motif and SMSS in the 2/3 fragment might serve as binding sites for PKC and -arrestin, respectively (37, 49).”
Background
β-Arrestins bind and decrease cell-surface abundance of the Na + /H + exchanger NHE5 isoform
Szabó, E. Z., Numata, M., Lukashova, V., Iannuzzi, P., & Orlowski, J. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0407444102 · Cited by 40
Non-synonymous single-nucleotide variations of the human oxytocin receptor gene and autism spectrum disorders: a case–control study in a Japanese population and functional analysis
Ma, W.-J., Hashii, M., Munesue, T., Hayashi, K., Yagi, K., Yamagishi, M., Higashida, H., & Yokoyama, S. (2013) · Molecular Autism · doi:10.1186/2040-2392-4-22 · Cited by 46
“The amino acid variation R376G/C is located in the intracellular carboxy (C)-terminal tail of the receptor protein, which is critical for desensitization, internalization, and recycling of the OXTR, as in many other GPCRs [9-13].”
BackgroundInfluential
Internalization of the human CRF receptor 1 is independent of classical phosphorylation sites and of β‐arrestin 1 recruitment
Rasmussen, T. N., Novak, I., & Nielsen, S. M. (2004) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.2004.04371.x · Cited by 40
Beneath the surface: endosomal GPCR signaling
Flores-Espinoza, E., & Thomsen, A. R. B. (2024) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2024.03.006 · Cited by 46
Biological properties and functional determinants of the urotensin II receptor
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Agonist-biased Trafficking of Somatostatin Receptor 2A in Enteric Neurons
Zhao, P., Canals, M., Murphy, J. E., Klingler, D., Eriksson, E. M., Pelayo, J., Hardt, M., Bunnett, N. W., & Poole, D. P. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.496414 · Cited by 39
Differential Regulation of Endosomal GPCR/β-Arrestin Complexes and Trafficking by MAPK
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“This contrasted with wild type -arrestin, which, as we showed previously, can be recruited at the plasma membrane upon agonist activation of 2AR, but does not internalize into endosomes with the receptor (29, 30).”
Background
Endothelin-Converting Enzyme-1 Degrades Internalized Somatostatin-14
Roosterman, D., Kempkes, C., Cottrell, G. S., Padilla, B. E., Bunnett, N. W., Turck, C. W., & Steinhoff, M. S. (2008) · Endocrinology · doi:10.1210/en.2007-1628 · Cited by 39
“They are functionally characterized by a long-lasting sequestration after stimulation with high concentrations of the agonist (8, 9).”
Individual phosphorylation sites at the C-terminus of the apelin receptor play different roles in signal transduction
Chen, J., Chen, X., Li, S., Jiang, Y., Mao, H., Zhang, R., Ji, B., Yan, M., Cai, X., & Wang, C. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101629 · Cited by 39
Neurokinin-1 versus mu-opioid receptor binding in rat nucleus tractus solitarius after single and recurrent intermittent hypoxia
Laferrière, A., Liu, J., & Moss, I. R. (2002) · Brain Research Bulletin · doi:10.1016/s0361-9230(02)00915-2 · Cited by 39

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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