Functional rewiring of G protein-coupled receptor signaling in human labor

Abigail R. Walker; Camilla B. Larsen; Samit Kundu; Christina Stavrinidis; Sung Hye Kim; Asuka Inoue; David F. Woodward; Yun S. Lee; Roberta Migale; David A. MacIntyre; Vasso Terzidou; Francesca Fanelli; Shirin Khanjani; Phillip R. Bennett; Aylin C. Hanyaloglu

doi:10.1016/j.celrep.2022.111318

Functional rewiring of G protein-coupled receptor signaling in human labor

Abigail R. Walker, Camilla B. Larsen, Samit Kundu, Christina Stavrinidis, Sung Hye Kim, Asuka Inoue, David F. Woodward, Yun S. Lee, Roberta Migale, David A. MacIntyre, Vasso Terzidou, Francesca Fanelli, Shirin Khanjani, Phillip R. Bennett^*, Aylin C. Hanyaloglu^*

^*此作品的通信作者

研究成果: 期刊稿件 › 文章 › 同行評審

5 引文斯高帕斯（Scopus）

摘要

Current strategies to manage preterm labor center around inhibition of uterine myometrial contractions, yet do not improve neonatal outcomes as they do not address activation of inflammation. Here, we identify that during human labor, activated oxytocin receptor (OTR) reprograms the prostaglandin E2 receptor, EP2, in the pregnant myometrium to suppress relaxatory/Gαs-cAMP signaling and promote pro-labor/inflammatory responses via altered coupling of EP2 from Gαq/11 to Gαi/o. The ability of EP2 to signal via Gαi/o is recapitulated with in vitro OT and only following OTR activation, suggesting direct EP2-OTR crosstalk. Super-resolution imaging with computational modeling reveals OT-dependent reorganization of EP2-OTR complexes to favor conformations for Gαi over Gαs activation. A selective EP2 ligand, PGN9856i, activates the relaxatory/Gαs-cAMP pathway but not the pro-labor/inflammatory responses in term-pregnant myometrium, even following OT. Our study reveals a mechanism, and provides a potential therapeutic solution, whereby EP2-OTR functional associations could be exploited to delay preterm labor.

原文	英語
文章編號	111318
期刊	Cell Reports
卷	40
發行號	10
DOIs	https://doi.org/10.1016/j.celrep.2022.111318
出版狀態	已出版 - 06 09 2022
對外發佈	是

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© 2022 The Author(s)

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10.1016/j.celrep.2022.111318

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Walker, A. R., Larsen, C. B., Kundu, S., Stavrinidis, C., Kim, S. H., Inoue, A., Woodward, D. F., Lee, Y. S., Migale, R., MacIntyre, D. A., Terzidou, V., Fanelli, F., Khanjani, S., Bennett, P. R., & Hanyaloglu, A. C. (2022). Functional rewiring of G protein-coupled receptor signaling in human labor. Cell Reports, 40(10), 文章 111318. https://doi.org/10.1016/j.celrep.2022.111318

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title = "Functional rewiring of G protein-coupled receptor signaling in human labor",

abstract = "Current strategies to manage preterm labor center around inhibition of uterine myometrial contractions, yet do not improve neonatal outcomes as they do not address activation of inflammation. Here, we identify that during human labor, activated oxytocin receptor (OTR) reprograms the prostaglandin E2 receptor, EP2, in the pregnant myometrium to suppress relaxatory/Gαs-cAMP signaling and promote pro-labor/inflammatory responses via altered coupling of EP2 from Gαq/11 to Gαi/o. The ability of EP2 to signal via Gαi/o is recapitulated with in vitro OT and only following OTR activation, suggesting direct EP2-OTR crosstalk. Super-resolution imaging with computational modeling reveals OT-dependent reorganization of EP2-OTR complexes to favor conformations for Gαi over Gαs activation. A selective EP2 ligand, PGN9856i, activates the relaxatory/Gαs-cAMP pathway but not the pro-labor/inflammatory responses in term-pregnant myometrium, even following OT. Our study reveals a mechanism, and provides a potential therapeutic solution, whereby EP2-OTR functional associations could be exploited to delay preterm labor.",

keywords = "CP: Cell biology, EP2, G protein-coupled receptor, crosstalk, heteromer, myometrium, oxytocin, pregnancy, preterm labor",

author = "Walker, {Abigail R.} and Larsen, {Camilla B.} and Samit Kundu and Christina Stavrinidis and Kim, {Sung Hye} and Asuka Inoue and Woodward, {David F.} and Lee, {Yun S.} and Roberta Migale and MacIntyre, {David A.} and Vasso Terzidou and Francesca Fanelli and Shirin Khanjani and Bennett, {Phillip R.} and Hanyaloglu, {Aylin C.}",

note = "Publisher Copyright: {\textcopyright} 2022 The Author(s)",

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doi = "10.1016/j.celrep.2022.111318",

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AU - Walker, Abigail R.

AU - Larsen, Camilla B.

AU - Kundu, Samit

AU - Stavrinidis, Christina

AU - Kim, Sung Hye

AU - Inoue, Asuka

AU - Woodward, David F.

AU - Lee, Yun S.

AU - Migale, Roberta

AU - MacIntyre, David A.

AU - Terzidou, Vasso

AU - Fanelli, Francesca

AU - Khanjani, Shirin

AU - Bennett, Phillip R.

AU - Hanyaloglu, Aylin C.

PY - 2022/9/6

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N2 - Current strategies to manage preterm labor center around inhibition of uterine myometrial contractions, yet do not improve neonatal outcomes as they do not address activation of inflammation. Here, we identify that during human labor, activated oxytocin receptor (OTR) reprograms the prostaglandin E2 receptor, EP2, in the pregnant myometrium to suppress relaxatory/Gαs-cAMP signaling and promote pro-labor/inflammatory responses via altered coupling of EP2 from Gαq/11 to Gαi/o. The ability of EP2 to signal via Gαi/o is recapitulated with in vitro OT and only following OTR activation, suggesting direct EP2-OTR crosstalk. Super-resolution imaging with computational modeling reveals OT-dependent reorganization of EP2-OTR complexes to favor conformations for Gαi over Gαs activation. A selective EP2 ligand, PGN9856i, activates the relaxatory/Gαs-cAMP pathway but not the pro-labor/inflammatory responses in term-pregnant myometrium, even following OT. Our study reveals a mechanism, and provides a potential therapeutic solution, whereby EP2-OTR functional associations could be exploited to delay preterm labor.

AB - Current strategies to manage preterm labor center around inhibition of uterine myometrial contractions, yet do not improve neonatal outcomes as they do not address activation of inflammation. Here, we identify that during human labor, activated oxytocin receptor (OTR) reprograms the prostaglandin E2 receptor, EP2, in the pregnant myometrium to suppress relaxatory/Gαs-cAMP signaling and promote pro-labor/inflammatory responses via altered coupling of EP2 from Gαq/11 to Gαi/o. The ability of EP2 to signal via Gαi/o is recapitulated with in vitro OT and only following OTR activation, suggesting direct EP2-OTR crosstalk. Super-resolution imaging with computational modeling reveals OT-dependent reorganization of EP2-OTR complexes to favor conformations for Gαi over Gαs activation. A selective EP2 ligand, PGN9856i, activates the relaxatory/Gαs-cAMP pathway but not the pro-labor/inflammatory responses in term-pregnant myometrium, even following OT. Our study reveals a mechanism, and provides a potential therapeutic solution, whereby EP2-OTR functional associations could be exploited to delay preterm labor.

KW - CP: Cell biology

KW - EP2

KW - G protein-coupled receptor

KW - crosstalk

KW - heteromer

KW - myometrium

KW - oxytocin

KW - pregnancy

KW - preterm labor

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DO - 10.1016/j.celrep.2022.111318

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AN - SCOPUS:85137300283

SN - 2211-1247

VL - 40

JO - Cell Reports

JF - Cell Reports

IS - 10

M1 - 111318

ER -

Functional rewiring of G protein-coupled receptor signaling in human labor

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