Functional rewiring of G protein-coupled receptor signaling in human labor.
Functional rewiring of G protein-coupled receptor signaling in human labor.
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DOI：
10.1016/j.celrep.2022.111318
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发表时间：
2022-09-06
期刊：
影响因子：
8.8
通讯作者：
Hanyaloglu, Aylin C.
中科院分区：
文献类型：
--
作者：
Walker, Abigail R.;Larsen, Camilla B.;Kundu, Samit;Stavrinidis, Christina;Kim, Sung Hye;Inoue, Asuka;Woodward, David F.;Lee, Yun S.;Migale, Roberta;Macntyre, David A.;Terzidou, Vasso;Fanelli, Francesca;Khanjani, Shirin;Bennet, Philip R.;Hanyaloglu, Aylin C.
目前管理早产的策略主要集中在抑制子宫肌层收缩，但由于没有解决炎症激活的问题，并没有改善新生儿的结局。在此，我们发现，在人类分娩过程中，激活的催产素受体（OTR）会对妊娠期子宫肌层中的前列腺素E2受体EP2进行重编程，抑制松弛性/Gαs - 环磷酸腺苷（cAMP）信号传导，并通过改变EP2从与Gαq/11偶联转变为与Gαi/o偶联来促进分娩相关/炎症反应。EP2通过Gαi/o进行信号传导的能力在体外催产素（OT）作用下且仅在OTR激活后得以重现，这表明EP2和OTR之间存在直接的相互作用。通过计算建模的超高分辨率成像显示，OT依赖的EP2 - OTR复合物的重组有利于Gαi激活而非Gαs激活的构象。一种选择性的EP2配体PGN9856i可激活松弛性/Gαs - cAMP通路，但在足月妊娠的子宫肌层中，即使在OT作用后也不会激活分娩相关/炎症反应。我们的研究揭示了一种机制，并提供了一种潜在的治疗方案，即可以利用EP2 - OTR的功能关联来延迟早产。
在人类分娩过程中，EP2的活性朝着促炎通路被重编程
催产素下调EP2 - Gαs信号传导，并将EP2 - Gαq/11信号传导转换为Gαi/o
EP2/OTR异源四聚体被催产素重组成有利于Gαi的构象
EP2激动剂PGN9856i即使在催产素处理后也不会激活分娩相关信号
前列腺素受体EP2在妊娠期维持子宫肌层的静止状态。沃克等人表明，在人类分娩过程中，EP2信号传导因与激活的催产素受体的功能性相互作用而转向炎症模式。一种EP2配体PGN9856i对这种相互作用有“抵抗力”，可用于延迟早产。
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. EP2 activity is reprogrammed toward pro-inflammatory pathways during human labor Oxytocin downregulates EP2-Gαs signaling and switches EP2-Gαq/11 signaling to Gαi/o EP2/OTR heterotetramers are reorganized by oxytocin to conformations favoring Gαi EP2 agonist PGN9856i does not activate pro-labor signals even after oxytocin treatment The prostanoid receptor EP2 maintains myometrial quiescence during pregnancy. Walker et al. show that during human labor, EP2 signaling switches toward an inflammatory profile driven by functional crosstalk with the activated oxytocin receptor. An EP2 ligand, PGN9856i, is “resistant” to this crosstalk and could be exploited to delay preterm labor.
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影响因子：
14.8
作者：
Albizu L;Cottet M;Kralikova M;Stoev S;Seyer R;Brabet I;Roux T;Bazin H;Bourrier E;Lamarque L;Breton C;Rives ML;Newman A;Javitch J;Trinquet E;Manning M;Pin JP;Mouillac B;Durroux T
通讯作者：
Durroux T
DOI：
10.1136/bjophthalmol-2020-317762
发表时间：
2021-11
期刊：
The British journal of ophthalmology
影响因子：
--
作者：
Bertrand JA;Woodward DF;Sherwood JM;Wang JW;Overby DR
通讯作者：
Overby DR
影响因子：
5.8
作者：
Casarini L;Lazzaretti C;Paradiso E;Limoncella S;Riccetti L;Sperduti S;Melli B;Marcozzi S;Anzivino C;Sayers NS;Czapinski J;Brigante G;Potì F;La Marca A;De Pascali F;Reiter E;Falbo A;Daolio J;Villani MT;Lispi M;Orlando G;Klinger FG;Fanelli F;Rivero-Müller A;Hanyaloglu AC;Simoni M
通讯作者：
Simoni M
影响因子：
5.8
作者：
EUROPEFINNER, GN;PHANEUF, S;BERNAL, AL
通讯作者：
BERNAL, AL
影响因子：
64.8
作者：
Kang Y;Kuybeda O;de Waal PW;Mukherjee S;Van Eps N;Dutka P;Zhou XE;Bartesaghi A;Erramilli S;Morizumi T;Gu X;Yin Y;Liu P;Jiang Y;Meng X;Zhao G;Melcher K;Ernst OP;Kossiakoff AA;Subramaniam S;Xu HE
通讯作者：
Xu HE