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

Cell Rep. 2022 Sep 6;40(10):111318. doi: 10.1016/j.celrep.2022.111318.

Authors

Affiliations

¹ Institute of Reproductive and Developmental Biology, Department Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
² Institute of Reproductive and Developmental Biology, Department Metabolism, Digestion and Reproduction, Imperial College London, London, UK; March of Dimes European Preterm Birth Research Centre, Imperial College London, London, UK.
³ Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
⁴ Department of Bioengineering, Imperial College London, London, UK.
⁵ Institute of Reproductive and Developmental Biology, Department Metabolism, Digestion and Reproduction, Imperial College London, London, UK; Stem Cell Biology and Developmental Genetics Laboratory, The Francis Crick Institute, London, UK.
⁶ Department Life Sciences, University of Modena and Reggio Emilia, via Campi 103, 41125 Modena, Italy; Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, via Campi 287, 41125 Modena, Italy.
⁷ Institute of Reproductive and Developmental Biology, Department Metabolism, Digestion and Reproduction, Imperial College London, London, UK; Reproductive Medicine Unit, University College London Hospital, London, UK.
⁸ Institute of Reproductive and Developmental Biology, Department Metabolism, Digestion and Reproduction, Imperial College London, London, UK; March of Dimes European Preterm Birth Research Centre, Imperial College London, London, UK. Electronic address: p.bennett@imperial.ac.uk.
⁹ Institute of Reproductive and Developmental Biology, Department Metabolism, Digestion and Reproduction, Imperial College London, London, UK. Electronic address: a.hanyaloglu@imperial.ac.uk.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Female
Humans
Infant, Newborn
Labor, Obstetric* / metabolism
Myometrium / metabolism
Obstetric Labor, Premature*
Pregnancy
Receptors, Oxytocin
Uterine Contraction / physiology

Substances

Receptors, Oxytocin

Grants and funding

DH_/Department of Health/United Kingdom