Naturally Occurring Genetic Variants in the Oxytocin Receptor Alter Receptor Signaling Profiles.

Area of Science:

• Pharmacogenomics
• Molecular Endocrinology
• Obstetrics and Gynecology

Background:

• Oxytocin is vital for uterine contractions and preventing postpartum hemorrhage.
• Patient response to oxytocin varies significantly, necessitating dose adjustments.
• Genetic factors influencing oxytocin receptor (OXTR) function are not fully understood.

Purpose of the Study:

• To investigate the functional impact of common genetic variants in the OXTR gene on oxytocin signaling and receptor behavior.
• To elucidate mechanisms underlying patient variability in response to oxytocin therapy.

Main Methods:

• Screening of 11 prevalent missense OXTR genetic variants.
• Assessing oxytocin-induced calcium signaling and beta-arrestin recruitment.
• Evaluating OXTR cell membrane trafficking, desensitization, and internalization.
• Utilizing molecular dynamics simulations.

Main Results:

• Five OXTR variants (V45L, P108A, L206V, V281M, E339K) altered oxytocin signaling or beta-arrestin recruitment.
• P108A and L206V enhanced membrane localization; V281M and E339K caused retention.
• E339K impaired activation, internalization, and desensitization; V281M decreased activation.
• V45L and P108A impaired beta-arrestin recruitment and internalization, potentially due to inhibited intracellular loop extension.

Conclusions:

• Specific OXTR genetic variants significantly affect oxytocin receptor function, including signaling, trafficking, and desensitization.
• These functional changes provide mechanistic insights into variable clinical responses to oxytocin.
• Understanding OXTR variants may inform personalized oxytocin dosing strategies in clinical practice.