Molecular evolution of the oxytocin-oxytocin receptor system in eutherians

Oxytocin (OXT) is a nine-amino-acid peptide hormone that is mainly released at the times of uterine contractions during parturition and milk ejection during lactation, whereas a similar peptide hormone, arginine vasopressin, primarily exerts direct antidiuretic action on the kidney and causes vasoconstriction of the peripheral vessels. The genes coding for these peptides are tandemly located on the same chromosome. A tandem duplication occurring in the common ancestor of jawed vertebrates has been proposed as responsible. In contrast to the two peptide hormones, only one oxytocin receptor (OXTR) but three arginine vasopressin receptors (AVPR1A, AVPR1B, and AVPR2) are known; these receptors probably arose from two rounds of genome duplication in the common ancestor of vertebrates. In this study, we addressed the molecular evolution of the OXT-OXTR system in eutherians. Our analyses suggest that an amino acid change from isoleucine to lysine on the eighth site (I8L) of the peptide, which corresponded to a change from mesotocin to OXT, had occurred during the common ancestral lineage of eutherians. At around the same time that the emergence of OXT occurred, functional constraints on the OXT receptor (pre-OXTR) might have relaxed, and a series of nonsynonymous substitutions might have accumulated. Only a few of these nonsynonymous substitutions might have contributed to reestablishing the molecular relationship between the OXT ligand and its receptor, after which functional constraints on the OXTR were reinstated. Since the OXT-OXTR system plays an important role in eutherians, the evolution of the OXT-OXTR system was probably an essential component of the genesis of the eutherian signature.