Comparative analyses of signal transduction in oxytocin receptor in primates

Abstract

Oxytocin (OT) and its receptor (OTR) are part of a system responsible for multiple functions like stimulating uterine contractions, milk ejection, social bonds between parents and offspring, pair bonds, and affiliative social interactions. Disabilities in in the interaction OT and OTR have clinical implications, since labor to behavioral disorders. The OT universal amino acid sequence conservation across the most mammalian species has an exception within Neotropical primates, where recently six new OT variants were identified to date. Concomitantly, a strong coevolutionary relationship between ligand and receptor variation has been demonstrated. These coevolutionary process has a potential to modify cell signaling cascades and, consequently, to influence in species-specific social behaviors. Leu8OT (oxytocin with a leucine at the eighth position of nonapeptide) is the most common form of OT in mammals, including humans.Two of the most notable variants are Pro8OT (proline instead of leucine at the eighth position) which was observed in the genus Callithrix (marmosets) and Val3Pro8OT (a valine instead of isoleucine at the third position) that was observed in the genus Saguinus (tamarins). In previous research in our laboratory was described a connection between the variations observed (Pro8OT and Val3Pro8OT) with biparental care and social monogamy, since these species show a higher proportion of expression of these behavioral spectrum. At the signaling level, the marmoset OTR shows a significantly higher efficacy in the ²-arrestin-2 recruitment and G protein activation when compared with the human OTR.Taking into account all the effects of variants on the OT-OTR signaling cascade, the goal of this project is to determine the molecular mechanisms involved in the coevolutionary process in the oxytocin system in primates at cellular level. To achieve this goal, we will analyze the impact of the human and marmoset genetic coding differences of OTR on cell signaling processes using site-directed mutagenesis and bioluminescence resonance energy transfer (BRET)- based biosensors. This will provide enlightenment oxytocin signaling cascade and reveal important and necessary approach for developing a potential pharmacotherapy. (AU)