The oxytocin receptor antagonist atosiban inhibits cell growth via a “biased agonist” mechanism
Open accessAbstract
In human myometrial cells, the promiscuous coupling of the oxytocin receptors (OTRs) to G(q) and G(i) leads to contraction. However, the activation of OTRs coupled to different G protein pathways can also trigger opposite cellular responses, e.g. OTR coupling to G(i) inhibits, whereas its coupling to G(q) stimulates, cell proliferation. Drug analogues capable of promoting a selective receptor-G protein coupling may be of great pharmacological and clinical importance because they may target only one specific signal transduction pathway. Here, we report that atosiban, an oxytocin derivative that acts as a competitive antagonist on OTR/G(q) coupling, displays agonistic properties on OTR/G(i) coupling, as shown by specific (35)S-labeled guanosine 5'-3-O-(thio) trisphosphate ([(35)S]GTPgammaS) binding. Moreover, atosiban, by acting on a G(i)-mediated pathway(,) inhibits cell growth of HEK293 and Madin-Darby canine kidney cells stably transfected with OTRs and of DU145 prostate cancer cells expressing endogenous OTRs. Notably, atosiban leads to persistent ERK1/2 activation and p21(WAF1/CIP1) induction, the same signaling events leading to oxytocin-mediated cell growth inhibition via a G(i) pathway. Finally, atosiban exposure did not cause OTR internalization and led to only a modest decrease (20%) in the number of high affinity cell membrane OTRs, two observations consistent with the finding that atosiban did not lead to any desensitization of the oxytocin-induced activation of the G(q)-phospholipase C pathway. Taken together, these observations indicate that atosiban acts as a "biased agonist" of the human OTRs and thus belongs to the class of compounds capable of selectively discriminating only one among the multiple possible active conformations of a single G protein-coupled receptor, thereby leading to the selective activation of a unique intracellular signal cascade.
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Some OTR antagonists, such as atosiban, can activate selective Gi pathways.
“some OTR antagonists, such as atosiban, can activate selective Gi pathways (36, 38).”
From Oxytocin receptors in the anteromedial bed nucleus of the stria terminalis promote stress-induced social avoidance in female California mice (2018) · cites this paper as [38]
Atosiban activates Gi-mediated pathways in vitro and in vivo.
“Interestingly, the OTR ligand atosiban, considered to be an OTR antagonist, actually activates Gi-mediated pathways in vitro (36, 38) and in vivo (57).”
From Oxytocin receptors in the anteromedial bed nucleus of the stria terminalis promote stress-induced social avoidance in female California mice (2018) · cites this paper as [38]
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- Authors
- Reversi, A., Rimoldi, V., Marrocco, T., Cassoni, P., Bussolati, G., Parenti, M., & Chini, B.
- Affiliations
- National Research Council (IT)
- University of Turin (IT)
- University of Milano-Bicocca (IT)
- Corresponding author
- Chini, Bice
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-04
- Volume
- 280
- Issue
- 16
- Pages
- 16311-16318
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1991442209
- Cited by
- 139
- References
- 45
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 4 · 2023: 3 · 2022: 7 · 2021: 11 · 2020: 5 · 2019: 11 · 2018: 7 · 2017: 4 · 2016: 2 · 2015: 6 · 2014: 1 · 2013: 8 · 2012: 8
- FWCI
- 4.02
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, cc-by)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Keywords
- atosiban, oxytocin receptor, biased agonism, receptor-G protein coupling, Gq coupling, cell growth inhibition, ERK1/2 activation, p21, receptor internalization, receptor desensitization, phospholipase C signaling, prostate cancer cells, myometrial cells
- MeSH terms
- Humans, Time Factors, Tritium, Vasotocin, Gene Transfer Techniques, Receptors, Oxytocin, Cell Proliferation
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