The oxytocin receptor (OTR) is a G protein-coupled receptor (GPCR) implicated in key physiological processes such as reproduction, social behaviour and cognition.[1] It is a promising therapeutic target for conditions including autism, pain and several cancers.[2,3] Recent findings have revealed that OTR forms heterodimers with other GPCRs, notably the dopamine D2 receptor (D2R), in various brain regions, suggesting a more complex and nuanced signalling network.[4] However, a major challenge in studying OTR biology remains the lack of selective antibodies and functional probes, hindering efforts to map OTR expression and elucidate the significance of receptor heterodimerization.
To address these challenges, we developed a set of innovative molecular tools for probing the OTR signalling system. Through solid-phase peptide synthesis and organic chemistry, we developed potent, selective fluorescent peptide tracers capable of OTR detection and activation. These tracers are ultrabright, fixable, and exhibit over 100-fold selectivity for OTR, enabling robust application in advanced techniques such as confocal microscopy and single particle tracking, as well as flow cytometry. Additionally, we developed heterobivalent ligands targeting OTR-D2R heterodimers and are applying different pharmacological assays to investigate how dimerisation influences downstream signalling and biological responses, including second messenger-based assays and bioluminescence resonance energy transfer (BRET) assays. This will provide deeper insights into the physiological role of OTR-D2R interactions.
Our molecular tools represent a significant advancement for the field, offering unprecedented resolution in mapping OTR distribution and functionality. These probes not only enhance our understanding of OTR signalling but may also contribute to the development of novel therapeutic strategies for OTR-related diseases.