Attenuation of oxytocin and serotonin 2A receptor signaling through novel heteroreceptor formation

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dc.contributor.authorChruścicka, Barbara
dc.contributor.authorWallace Fitzsimons, Shauna E.
dc.contributor.authorBorroto-Escuela, Dasiel O.
dc.contributor.authorDruelle, Clémentine
dc.contributor.authorStamou, Panagiota
dc.contributor.authorNally, Kenneth
dc.contributor.authorDinan, Timothy G.
dc.contributor.authorCryan, John F.
dc.contributor.authorFuxe, Kjell
dc.contributor.authorSchellekens, Harriët
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderMedicinska Forskningsrådeten
dc.contributor.funderHjärnfondenen
dc.contributor.funderKarolinska Instituteten
dc.date.accessioned2019-08-29T08:36:17Z
dc.date.available2019-08-29T08:36:17Z
dc.date.issued2019-04-30
dc.date.updated2019-08-28T15:56:19Z
dc.description.abstractThe oxytocin receptor (OTR) and the 5-hydroxytryptamine 2A receptor (5-HTR2A) are expressed in similar brain regions modulating central pathways critical for social and cognition-related behaviors. Signaling crosstalk between their endogenous ligands, oxytocin (OT) and serotonin (5-hydroxytryptamine, 5-HT), highlights the complex interplay between these two neurotransmitter systems and may be indicative of the formation of heteroreceptor complexes with subsequent downstream signaling changes. In this study, we assess the possible formation of OTR-5HTR2A heteromers in living cells and the functional downstream consequences of this receptor–receptor interaction. First, we demonstrated the existence of a physical interaction between the OTR and 5-HTR2Ain vitro, using a flow cytometry-based FRET approach and confocal microscopy. Furthermore, we investigated the formation of this specific heteroreceptor complex ex vivo in the brain sections using the Proximity Ligation Assay (PLA). The OTR-5HTR2A heteroreceptor complexes were identified in limbic regions (including hippocampus, cingulate cortex, and nucleus accumbens), key regions associated with cognition and social-related behaviors. Next, functional cellular-based assays to assess the OTR-5HTR2A downstream signaling crosstalk showed a reduction in potency and efficacy of OT and OTR synthetic agonists, carbetocin and WAY267464, on OTR-mediated Gαq signaling. Similarly, the activation of 5-HTR2A by the endogenous agonist, 5-HT, also revealed attenuation in Gαq-mediated signaling. Finally, altered receptor trafficking within the cell was demonstrated, indicative of cotrafficking of the OTR/5-HTR2A pair. Overall, these results constitute a novel mechanism of specific interaction between the OT and 5-HT neurotransmitters via OTR-5HTR2A heteroreceptor formation and provide potential new therapeutic strategies in the treatment of social and cognition-related diseases.en
dc.description.sponsorshipMedicinska Forskningsrådet (Swedish Medical Research Council (62X-00715-50-3)); Hjärnfonden (F02018-0286);en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationChruścicka, B., Wallace Fitzsimons, S. E., Borroto-Escuela, D. O., Druelle, C., Stamou, P., Nally, K., Dinan, T. G., Cryan, J. F., Fuxe, K. and Schellekens, H. (2019) 'Attenuation of Oxytocin and Serotonin 2A Receptor Signaling through Novel Heteroreceptor Formation', ACS Chemical Neuroscience, 10(7), pp. 3225-3240. doi: 10.1021/acschemneuro.8b00665en
dc.identifier.doi10.1021/acschemneuro.8b00665en
dc.identifier.endpage3240en
dc.identifier.issn1948-7193
dc.identifier.issued7en
dc.identifier.journaltitleACS Chemical Neuroscienceen
dc.identifier.startpage3225en
dc.identifier.urihttps://hdl.handle.net/10468/8406
dc.identifier.volume10en
dc.language.isoenen
dc.publisherAmerican Chemical Society, ACSen
dc.relation.projectinfo:eu-repo/grantAgreement/SFI/SFI Research Centres/12/RC/2273/IE/Alimentary Pharmabiotic Centre (APC) - Interfacing Food & Medicine/en
dc.relation.urihttps://pubs.acs.org/doi/abs/10.1021/acschemneuro.8b00665
dc.rights© 2019 American Chemical Society. This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Chemical Neuroscience, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/abs/10.1021/acschemneuro.8b00665en
dc.subjectOTRen
dc.subject5-HTR2Aen
dc.subjectHeteroreceptor complexesen
dc.subjectfcFRETen
dc.subjectPLAen
dc.subjectGαq-mediated signaling crosstalken
dc.subjectOxytocin receptoren
dc.titleAttenuation of oxytocin and serotonin 2A receptor signaling through novel heteroreceptor formationen
dc.typeArticle (peer-reviewed)en
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