Spatial-temporal regulation of the prostanoid receptor EP2 co-ordinates PGE2-mediated cAMP signaling in decidualizing human endometrium

被引：0

作者：

Brighton, Paul J. ^{[1
]}

Walker, Abigail R. ^{[2
]}

Mann, Oliver ^{[1
]}

Kong, Chow-Seng ^{[1
]}

Lucas, Emma S. ^{[1
,3
]}

Vrljicak, Pavle ^{[1
]}

Brosens, Jan J. ^{[1
,4
,5
]}

Hanyaloglu, Aylin C. ^{[2
]}

机构：

[1] Univ Warwick, Warwick Med Sch, Div Biomed Sci, Clin Sci Res Labs, Coventry CV2 2DX, England

[2] Inst Reprod & Dev Biol, Imperial Coll London, Dept Metab Digest & Reprod, London W12 0NN, England

[3] Univ Sheffield, Fac Hlth, Sch Med & Populat Hlth, Div Clin Med, Sheffield S10 2SF, England

[4] Univ Warwick, Ctr Early Life, Coventry CV4 7AL, England

[5] Univ Hosp Coventry & Warwickshire NHS Trust, Tommys Natl Ctr Miscarriage Res, Coventry CV2 2DX, England

来源：

ISCIENCE | 2024年 / 27卷 / 11期

基金：

英国生物技术与生命科学研究理事会;

关键词：

FOCAL ADHESION KINASE; IMMUNOHISTOCHEMICAL LOCALIZATION; RELAXIN; INTERNALIZATION; ENDOCYTOSIS; ENDOSOMES; TRAFFICKING; EXPRESSION; TRKA;

D O I：

10.1016/j.isci.2024.111170

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Decidualization denotes the differentiation of endometrial stromal cells into specialized decidual cells, essential for embryo implantation and pregnancy. The process requires coordination of progesterone and cAMP signaling, which converge on downstream transcription factors. PGE2 and relaxin, acting, respectively, through Gas-coupled GPCRs EP2 and RXFP1, are putative candidates for generating cAMP in differentiating stromal cells. Here, we show that PGE2 is less efficacious than relaxin in elevating intracellular cAMP levels in primary stromal cells but more effective at driving the expression of decidual genes. PGE2-and relaxin-induced cAMP generation involves receptor internalization, but EP2 is endocytosed into very early endosomes (VEEs). Perturbation of VEE machinery through depletion of key trafficking proteins; APPL1 and GIPC, dysregulates PGE2-dependent cAMP profiles and disrupts key decidual signaling pathways, resulting in a disordered differentiation response. We demonstrate that regulation of EP2 via internalization is essential for coordinated activation of the downstream signaling cascades that govern decidualization.

引用

页数：17