Abstract
The hormone oxytocin is commonly administered during childbirth to initiate and strengthen uterine contractions and prevent postpartum hemorrhage. However, patients have wide variation in the oxytocin dose required for a clinical response. To begin to uncover the mechanisms underlying this variability, we screened the 11 most prevalent missense genetic variants in the oxytocin receptor (OXTR) gene. We found that five variants, V45L, P108A, L206V, V281M, and E339K, significantly altered oxytocin-induced Ca2+ signaling or β-arrestin recruitment and proceeded to assess the effects of these variants on OXTR trafficking to the cell membrane, desensitization, and internalization. The variants P108A and L206V increased OXTR localization to the cell membrane, whereas V281M and E339K caused OXTR to be retained inside the cell. We examined how the variants altered the balance between OXTR activation and desensitization, which is critical for appropriate oxytocin dosing. The E339K variant impaired OXTR activation, internalization, and desensitization to roughly equal extents. In contrast, V281M decreased OXTR activation but had no effect on internalization and desensitization. V45L and P108A did not alter OXTR activation but did impair β-arrestin recruitment, internalization, and desensitization. Molecular dynamics simulations predicted that V45L and P108A prevent extension of the first intracellular loop of OXTR, thus inhibiting β-arrestin binding. Overall, our data suggest mechanisms by which OXTR genetic variants could alter clinical response to oxytocin.
Highlights
The hormone oxytocin is commonly administered during childbirth to initiate and strengthen uterine contractions and prevent postpartum hemorrhage
For labor induction and augmentation, maximal oxytocin infusion rates range from 2 milliunits/min to 40 milliunits/min.[3]
P108A and L206V increased the percentage of oxytocin receptor (OXTR) on the cell membrane, whereas V281M and E339K caused OXTR to be retained inside the cell
Summary
The hormone oxytocin is commonly administered during childbirth to initiate and strengthen uterine contractions and prevent postpartum hemorrhage. We found that five variants, V45L, P108A, L206V, V281M, and E339K, significantly altered oxytocin-induced Ca2+ signaling or β-arrestin recruitment and proceeded to assess the effects of these variants on OXTR trafficking to the cell membrane, desensitization, and internalization. We examined how the variants altered the balance between OXTR activation and desensitization, which is critical for appropriate oxytocin dosing. V45L and P108A did not alter OXTR activation but did impair β-arrestin recruitment, internalization, and desensitization. Release from intracellular stores, which promotes myometrial smooth muscle contraction.[10] OXTR signaling through Gq is counteracted by coupling to β-arrestin, which mediates desensitization and internalization of OXTR from the cell surface.[11−14] OXTR desensitization after oxytocin exposure may impair myometrial contractions, leading to adverse events including uterine atony and postpartum hemorrhage.[6−8]. Reinl et al and Grotegut et al identified single nucleotide OXTR variants in patients who required high or low doses of oxytocin to induce labor, but these studies were not powered to detect significant associations.[15,16] In an ex vivo study, one coding and one noncoding OXTR variant altered the oxytocin-induced contractions of uterine tissue strips isolated
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