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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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“10,44 In summary, GPCRs more than any other class of proteins have proven to be a rich source of therapeutic targets.”
β-Arrestin2-Mediated Internalization of Mammalian Odorant Receptors
Mashukova, A., Spehr, M., Hatt, H. H., & Neuhaus, E. M. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.2897-06.2006 · Cited by 110
“…in the C-terminal tail of GPCRs was described to be responsible for the agonist-dependent formation of high-affinity -arrestin complexes by binding of the phosphorylation recognition domain (arrestin) to the GRK-phosphorylated C terminus (receptor) (Gurevich and Benovic, 1997; Oakley et al., 2001).”
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Differential Signaling of the Endogenous Agonists at the β2-Adrenergic Receptor
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“2).((41,43)) Two studies have now established that ubiquitination of b-arrestin plays a central role in this process.”
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““Class A” GPCRs (e.g., β2 adrenergic receptor, B2R, μ-opioid receptor, neurokinin 3 receptor) have few phosphorylation sites, interact transiently with β-arrestin2 with low affi nity, and rapidly recycle (Oakley et al., 1999, 2000, 2001; Schmidlin et al., 2003).”
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“Such a saturating dose triggers desensitization, a process underlying the translocation of GFP: even at such high doses, the response is highly specific to potent agonists (Barak et al., 1997, 1999; Kim et al., 2001; Oakley et al., 2001).”
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“For many other GPCRs, such as those for angiotensin II, dopamine, serotonin, and adrenergic ligands, it is now accepted that there can be differential signaling, depending on the activating ligand.”
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“Phosphorylation of the intracellular tail may produce a local concentration of negative charges that promotes binding to the positively charged phosphorylation recognition domain of arrestin, thereby stabilizing the formation of the receptor-arrestin complex (39).”
BackgroundPlasma membrane preassociation drives β-arrestin coupling to receptors and activation
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“The first activation is transient (a few minutes); the second activation is more persistent (up to 1 h) and depends on the duration of the receptor endocytosis, which is much longer for class B than for class A receptors (Oakley et al., 2001).”
Recycling and Resensitization of the Neurokinin 1 Receptor
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Protein Complexes Involved in Heptahelical Receptor-Mediated Signal Transduction
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Role of Ubiquitination in Endocytic Trafficking of G‐Protein‐Coupled Receptors
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“This difference in β-arrestin behavior can be determined by the phosphorylation state of the GPCR cytoplasmic tail (98), but also by ubiquitination of the β-arrestin.”
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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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