人类分娩中 G 蛋白偶联受体信号的功能重排。
Functional rewiring of G protein-coupled receptor signaling in human labor.
机构信息
Institute of Reproductive and Developmental Biology, Department Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
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.
出版信息
Cell Rep. 2022 Sep 6;40(10):111318. doi: 10.1016/j.celrep.2022.111318.
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.
目前，针对早产的管理策略主要集中在抑制子宫平滑肌收缩上，但由于它们不能解决炎症的激活问题，因此并不能改善新生儿的结局。在这里，我们发现，在人类分娩过程中，激活的催产素受体（OTR）会重新编程妊娠子宫中的前列腺素 E2 受体 EP2，以抑制松弛性/Gαs-cAMP 信号转导，并通过 EP2 从 Gαq/11 到 Gαi/o 的偶联改变来促进产力/炎症反应。EP2 通过 Gαi/o 发出信号的能力可以通过体外 OT 重现，并且仅在 OTR 激活之后，这表明存在直接的 EP2-OTR 串扰。使用计算建模的超分辨率成像揭示了 OT 依赖性的 EP2-OTR 复合物的重排，以有利于 Gαi 而不是 Gαs 的激活构象。一种选择性的 EP2 配体 PGN9856i 在足月妊娠的子宫平滑肌中激活松弛性/Gαs-cAMP 通路，但不激活产力/炎症反应，即使在 OT 之后也是如此。我们的研究揭示了一种机制，并提供了一种潜在的治疗解决方案，即 EP2-OTR 的功能关联可以被利用来延迟早产。
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