TY - JOUR
T1 - Naturally Occurring Genetic Variants in the Oxytocin Receptor Alter Receptor Signaling Profiles
AU - Malik, Manasi
AU - Ward, Michael D.
AU - Fang, Yingye
AU - Porter, Justin R.
AU - Zimmerman, Maxwell I.
AU - Koelblen, Thomas
AU - Roh, Michelle
AU - Frolova, Antonina I.
AU - Burris, Thomas P.
AU - Bowman, Gregory R.
AU - Imoukhuede, Princess I.
AU - England, Sarah K.
N1 - Funding Information:
This study was funded by the National Institute of Child Health and Human Development (R01 HD088097 to S.K.E., R01 HD096737 to S.K.E. and P.I.I.) and by an AMAG Pharmaceuticals Research Grant in Prematurity and Pre-eclampsia (S.K.E.). M.M. is funded by T32 GM02700, TL1 TR002344, and F30 HD097925.
Publisher Copyright:
© 2021 American Chemical Society. All rights reserved.
PY - 2021/10/8
Y1 - 2021/10/8
N2 - 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.
AB - 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.
KW - molecular dynamics
KW - oxytocin receptor
KW - pharmacogenetics
KW - precision medicine
KW - variants of unknown significance
KW - β-arrestin
UR - http://www.scopus.com/inward/record.url?scp=85115767806&partnerID=8YFLogxK
U2 - 10.1021/acsptsci.1c00095
DO - 10.1021/acsptsci.1c00095
M3 - Article
C2 - 34661073
AN - SCOPUS:85115767806
SN - 2575-9108
VL - 4
SP - 1543
EP - 1555
JO - ACS Pharmacology and Translational Science
JF - ACS Pharmacology and Translational Science
IS - 5
ER -