The
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-HTR2A
in 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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.