Functional Effects of Oxytocin Receptor Post-translational Modifications

ABSTRACT Oxytocin plays a pivotal role in clinical obstetrics, commonly used for labor induction and augmentation. However, safe administration of oxytocin is challenging due to its wide therapeutic window, often leading to decreased uterine response with continuous exposure. Reduction in uterine contractility can lead to emergency cesarean delivery or contribute to post-partum hemorrhage – the leading cause of global maternal morbidity and mortality. To mitigate these issues, understanding the function of the oxytocin receptor (OXTR) is imperative. OXTR is a G-protein coupled receptor that undergoes post-translational modifications (PTMs), that can influence trafficking, function, and degradation of the receptor. Such PTMs include glycosylation, the covalent attachment of carbohydrates, and ubiquitination, the covalent attachment of ubiquitin proteins. This study aims to study the impact of glycosylation and ubiquitination on OXTR function through genetic and pharmacologic interventions. In Aim 1, I will elucidate the effects of glycosylation on OXTR abundance at the cell surface, oxytocin-binding, and OXTR signaling function. In Aim 2, I will determine the effects of ubiquitination on OXTR signaling function and degradation of the receptor. Ultimately, by determining mechanisms of N-glycosylation and ubiquitination that affect OXTR abundance at the cell surface, this work will uncover new targets to enhance OXTR response, through its trafficking, to oxytocin. In the long term, this work may lead to development of new strategies to decrease the rates of labor complications and maternal morbidity.