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

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/Gas-cAMP signaling and promote pro-labor/inflammatory re-sponses via altered coupling of EP2 from Gaq/11 to Gai/o. The ability of EP2 to signal via Gai/o is recapitu-lated with in vitro OT and only following OTR activation, suggesting direct EP2-OTR crosstalk. Super -reso-lution imaging with computational modeling reveals OT-dependent reorganization of EP2-OTR complexes to favor conformations for Gai over Gas activation. A selective EP2 ligand, PGN9856i, activates the relaxa-tory/Gas-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.