Leu8 and Pro8 oxytocin agonism differs across human, macaque, and marmoset vasopressin 1a receptors

Aaryn Mustoe,Jeffrey A French,Myron L Toews,Jack H Taylor,Nancy A Schulte

doi:10.1038/s41598-019-52024-9

Aaryn Mustoe, Jeffrey A French + Show 3 more

Open Access

https://doi.org/10.1038/s41598-019-52024-9

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Abstract

Oxytocin (OXT) is an important neuromodulator of social behaviors via activation of both oxytocin receptors (OXTR) and vasopressin (AVP) 1a receptors (AVPR1a). Marmosets are neotropical primates with a modified OXT ligand (Pro8-OXT), and this ligand shows significant coevolution with traits including social monogamy and litter size. Pro8-OXT produces more potent and efficacious responses at primate OXTR and stronger behavioral effects than the consensus mammalian OXT ligand (Leu8-OXT). Here, we tested whether OXT/AVP ligands show differential levels of crosstalk at primate AVPR1a. We measured binding affinities and Ca2+ signaling responses of AVP, Pro8-OXT and Leu8-OXT at human, macaque, and marmoset AVPR1a. We found that AVP binds with higher affinity than OXT across AVPR1a, and marmoset AVPR1a show a 10-fold lower OXT binding affinity compared to human and macaque AVPR1a. Both Leu8-OXT and Pro8-OXT produce a less efficacious response than AVP at human AVPR1a and higher efficacious response than AVP at marmoset AVPR1a. These data suggest that OXT might partially antagonize endogenous human AVPR1a signaling and enhance marmoset AVPR1a signaling. These findings aid in further understanding inconsistencies observed following systemic intranasal administration of OXT and provide important insights into taxon-specific differences in nonapeptide ligand/receptor coevolution and behavior.

Highlights

Oxytocin (OXT) is an important neuromodulator of social behaviors via activation of both oxytocin receptors (OXTR) and vasopressin (AVP) 1a receptors (AVPR1a)
The nonapeptide hormone family is present in most animal lineages[9,10], and OXT-like nonapeptides vary in structure across phyla at the second, third, fourth, or eighth amino acid (AA) position[11]
In mammals OXT plays a central role in reproduction and parental care, and the prevailing belief was that the OXT molecule was strictly conserved across mammals[12]

Summary

Introduction

Oxytocin (OXT) is an important neuromodulator of social behaviors via activation of both oxytocin receptors (OXTR) and vasopressin (AVP) 1a receptors (AVPR1a). One tantalizing explanation for this coevolution is that a change in the OXT molecule from the ancestral mammalian Leu8-OXT to Pro8-OXT (Pro[8] being the most prevalent AA substitution from the ancestral OXT) results in a significant structural alteration in the 8th AA position This change causes a ‘bent tail’ in the ligand that leads it to be more sterically constrained, and this tail portion of the OXT molecule is critical for OXT receptor binding and activation[18,20,21,22]. Pro8-OXT binds with higher affinity at primate OXTR (in both Pro8-OXT and Leu8-OXT expressing primates) and produces greater calcium signaling responses compared with Leu8-OXT24,25, but others have reported minimal signaling differences[23]

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