Molecular, biochemical and behavioural evidence for a novel oxytocin receptor and serotonin 2C receptor heterocomplex

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dc.contributor.authorChruścicka, Barbara
dc.contributor.authorCowan, Caitlin S. M.
dc.contributor.authorWallace Fitzsimons, Shauna E.
dc.contributor.authorBorroto-Escuela, Dasiel O.
dc.contributor.authorDruelle, Clémentine
dc.contributor.authorStamou, Panagiota
dc.contributor.authorBergmann, Cristian A.
dc.contributor.authorDinan, Timothy G.
dc.contributor.authorSlattery, David A.
dc.contributor.authorFuxe, Kjell
dc.contributor.authorCryan, John F.
dc.contributor.authorSchellekens, Harriët
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderNarodowym Centrum Naukien
dc.contributor.funderMedicinska Forskningsrådeten
dc.contributor.funderHjärnfondenen
dc.date.accessioned2022-05-12T14:15:49Z
dc.date.available2022-05-12T14:15:49Z
dc.date.issued2021-02
dc.date.updated2022-05-12T13:39:31Z
dc.description.abstractThe complexity of oxytocin-mediated functions is strongly associated with its modulatory effects on other neurotransmission systems, including the serotonin (5-hydroxytryptamine, 5-HT) system. Signalling between oxytocin (OT) and 5-HT has been demonstrated during neurodevelopment and in the regulation of specific emotion-based behaviours. It is suggested that crosstalk between neurotransmitters is driven by interaction between their specific receptors, particularly the oxytocin receptor (OTR) and the 5-hydroxytryptamine 2C receptor (5-HTR2C), but evidence for this and the downstream signalling consequences that follow are lacking. Considering the overlapping central expression profiles and shared involvement of OTR and 5-HTR2C in certain endocrine functions and behaviours, including eating behaviour, social interaction and locomotor activity, we investigated the existence of functionally active OTR/5-HTR2C heterocomplexes. Here, we demonstrate evidence for a potential physical interaction between OTR and 5-HTR2C in vitro in a cellular expression system using flow cytometry-based FRET (fcFRET). We could recapitulate this finding under endogenous expression levels of both receptors via in silico analysis of single cell transcriptomic data and ex vivo proximity ligation assay (PLA). Next, we show that co-expression of the OTR/5-HTR2C pair resulted in a significant depletion of OTR-mediated G alpha q-signalling and significant changes in receptor trafficking. Of note, attenuation of OTR-mediated downstream signalling was restored following pharmacological blockade of the 5-HTR2C. Finally, we demonstrated a functional relevance of this novel heterocomplex, in vivo, as 5-HTR2C antagonism increased OT-mediated hypoactivity in mice. Overall, we provide compelling evidence for the formation of functionally active OTR/5-HTR2C heterocomplexes, adding another level of complexity to OTR and 5-HTR2C signalling functionality.This article is part of the special issue on Neuropeptides.en
dc.description.sponsorshipNarodowym Centrum Nauki (Grant number 2019/03/X/NZ1/00607); Medicinska Forskningsrådet (Grant number 62X-00715-50-3); Hjärnfonden (Grant number F02018-0286)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.articleid108394en
dc.identifier.citationChruścicka, B., Cowan, C. S. M., Wallace Fitzsimons, S. E., Borroto-Escuela, D. O., Druelle, C. M., Stamou, P., Bergmann, C. A., Dinan, T. G., Slattery, D. A., Fuxe, K., Cryan, J. F. and Schellekens, H. (2021) 'Molecular, biochemical and behavioural evidence for a novel oxytocin receptor and serotonin 2C receptor heterocomplex', Neuropharmacology, 183, 108394, (17pp). doi: 10.1016/j.neuropharm.2020.108394en
dc.identifier.doi10.1016/j.neuropharm.2020.108394en
dc.identifier.endpage17en
dc.identifier.issn0028-3908
dc.identifier.journaltitleNeuropharmacologyen
dc.identifier.startpage1en
dc.identifier.urihttps://hdl.handle.net/10468/13173
dc.identifier.volume183en
dc.language.isoenen
dc.publisherElsevieren
dc.relation.projectinfo:eu-repo/grantAgreement/SFI/SFI Research Centres/12/RC/2273/IE/Alimentary Pharmabiotic Centre (APC) - Interfacing Food & Medicine/en
dc.rights© 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subject5-HT2C receptoren
dc.subjectIntranasal oxytocinen
dc.subjectSocial cognitionen
dc.subjectDevelopmental-hyperserotonemiaen
dc.subjectAdministered oxytocinen
dc.subjectVasopressin V1aen
dc.subjectAgonisten
dc.subjectLiganden
dc.subjectTraffickingen
dc.subjectActivationen
dc.titleMolecular, biochemical and behavioural evidence for a novel oxytocin receptor and serotonin 2C receptor heterocomplexen
dc.typeArticle (peer-reviewed)en
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