The DOI matches its Crossref record; 51 of the 51 references it cites were found in a registry or an index.
Intracellular trafficking of the human oxytocin receptor: Evidence of receptor recycling via a Rab4/Rab5 “short cycle.”
Abstract
As in the case of most G protein-coupled receptors, agonist stimulation of human oxytocin receptors (OTRs) leads to desensitization and internalization; however, little is known about the subsequent intracellular OTR trafficking, which is crucial for reestablishing agonist responsiveness. We examined receptor resensitization by first using HEK293T cells stably expressing human OTRs. Upon agonist activation, the receptors were almost completely sequestered inside intracellular compartments that were not labeled by lysosomal markers, thus indicating that the internalized receptors were not sorted to these degrading organelles. Binding and fluorescence assays showed that almost 85% of the receptors had returned to the cell surface after 4 h, by which time cell responsiveness to the agonist was also completely restored, as shown by measuring phospholipase C activation. Similar results were also obtained in the presence of cycloheximide, thus indicating that receptor recycling and not de novo receptor synthesis was responsible for the resensitization. Notably, very similar internalization and recycling kinetics were observed in endogenous OTRs expressed on myometrial cells. We also investigated the role of beta-arrestin2 in OTR recycling as these receptors have been previously classified as slowly or nonrecycling receptors on the basis of their stable association with this interacting protein. Our data suggest that the stable OTR/beta-arrestin2 interaction plays an important role in determining the rate of recycling of human OTRs, but does not determine the fate of endocytosed receptors. Subsequent investigations of receptor recycling pathways showed that OTRs localize in vesicles containing the Rab5 and Rab4 small GTPases (markers of the "short cycle"), whereas there was no colocalization with Rab11 (a marker of the "long cycle") or Rab7 (a marker of vesicles directed to endosomal/lysosomal compartments). Taken together, these data indicate that OTRs are capable of very efficient and complete resensitization due to receptor recycling via the short cycle.
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“It is unsurprising that higher concentrations of oxytocin are needed for behavioral effects than for peripheral effects.As in most G protein-coupled receptors, agonist stimulation of oxytocin receptors leads to desensitization (27).Receptors at peripheral sites are exposed to much lower concentrations of oxytocin (1-10pg/ml), than receptors in the brain (1), so will be more sensitive to it.”
From Intranasal Oxytocin: Myths and Delusions (2016) · cites this paper as [27]
In the citing paper
“Indeed, the oxytocin receptor is a G protein-coupled receptor and can undergo desensitisation and internalization after agonist application (Conti et al, 2009;Insel et al, 1992).”
From Chronic and acute intranasal oxytocin produce divergent social effects in mice (2014) · cites this paper as Conti et al, 2009
In the citing paper
“Thus, intranasal administration of OXT might act to increase the concentration of OXT beyond endogenous levels in a normal-functioning brain resulting in desensitisation and hence, down-regulation of OXTRs.”
From Chronic and acute intranasal oxytocin produce divergent social effects in mice (2014) · cites this paper as Conti et al, 2009
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Metadata
- Authors
- Conti, F., Sertic, S., Reversi, A., & Chini, B.
- Affiliations
- National Research Council (IT)
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2009-03
- Volume
- 296
- Issue
- 3
- Pages
- E532-E542
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W2115296867
- Cited by
- 113
- References
- 51
- Citations by year
- 2026: 9 · 2025: 3 · 2024: 6 · 2023: 6 · 2022: 11 · 2021: 12 · 2020: 10 · 2019: 7 · 2018: 8 · 2017: 7 · 2016: 3 · 2015: 6 · 2014: 2 · 2013: 6 · 2012: 4
- FWCI
- 2.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- 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 › Endocrine and Autonomic Systems › Neuroendocrine regulation and behavior
- Keywords
- oxytocin receptor, receptor recycling, short cycles, Rab4, Rab5, Rab11, Rab7, G protein-coupled receptor internalization, receptor resensitization, β-arrestin2, myometrium, phospholipase C, endosomal trafficking
- MeSH terms
- beta-Arrestins, rab11 GTP-Binding Proteins, Cell Line, Cell Membrane, Endocytosis, Female, Humans, Kidney, Lysosomes, Myometrium, Oxytocin, Receptors, Cell Surface, Tritium, Receptors, Oxytocin, Arrestins, rab GTP-Binding Proteins, rab4 GTP-Binding Proteins, rab5 GTP-Binding Proteins, Protein Transport
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