GPR30 Activation Opposes Estrogen-Dependent Uterine Growth via Inhibition of Stromal ERK1/2 and Estrogen Receptor Alpha (ERα) Phosphorylation Signals
GPR30 Activation Opposes Estrogen-Dependent Uterine Growth via Inhibition of Stromal ERK1/2 and Estrogen Receptor Alpha (ERα) Phosphorylation Signals
复制标题
DOI：
10.1210/en.2010-1368
复制
发表时间：
2011-04-01
期刊：
影响因子：
4.8
通讯作者：
Das, Sanjoy K.
中科院分区：
文献类型：
--
作者：
Gao, Fei;Ma, Xinghong;Das, Sanjoy K.
虽然雌二醇-17 β (E2)调控的早期和晚期子宫反应已经被很好地定义，但连接这些阶段的分子机制仍然知之甚少。我们之前已经证明e2调节的早期信号介导与雌激素受体(ER)- α的串扰，从而引发子宫晚期生长反应。G蛋白偶联受体（GPR30）参与E2介导的早期非基因组信号传导，尽管其在E2依赖性子宫生物学中的作用尚不清楚。通过G-1选择性激活GPR30，我们在这里展示了GPR30在调节早期信号事件中的新功能，包括抑制ERK1/2和ER α (Ser118)磷酸化信号，以及在E2的指导下扰动小鼠子宫的生长调节。我们观察到GPR30主要定位于子宫上皮细胞，其激活改变基因表达，介导间质室ERK1/2和ER α (Ser118)磷酸化信号的抑制，提示其参与旁分泌信号。重要的是，病毒驱动的GPR30操纵或ERK1/2激活的药理学抑制有效地改变e2依赖性子宫生长反应。总的来说，GPR30是E2对ER α依赖性子宫生长的负调节因子。我们的工作发现了一种新的gpr30调控的抑制事件，它可能在生理上与正常和病理情况下负平衡E2诱导的ER α依赖性子宫生长调节功能有关。（内分泌学152:1434-1447,2011）
Although estradiol-17 beta (E2)-regulated early and late phase uterine responses have been well defined, the molecular mechanisms linking the phases remain poorly understood. We have previously shown that E2-regulated early signals mediate cross talk with estrogen receptor (ER)-alpha to elicit uterine late growth responses. G protein-coupled receptor (GPR30) has been implicated in early nongenomic signaling mediated by E2, although its role in E2-dependent uterine biology is unclear. Using selective activation of GPR30 by G-1, we show here a new function of GPR30 in regulating early signaling events, including the inhibition of ERK1/2 and ER alpha (Ser118) phosphorylation signals and perturbation of growth regulation under the direction of E2 in the mouse uterus. We observed that GPR30 primarily localizes in the uterine epithelial cells, and its activation alters gene expression and mediates inhibition of ERK1/2 and ER alpha (Ser118) phosphorylation signals in the stromal compartment, suggesting a paracrine signaling is involved. Importantly, viral-driven manipulation of GPR30 or pharmacological inhibition of ERK1/2 activation effectively alters E2-dependent uterine growth responses. Overall, GPR30 is a negative regulator of ER alpha-dependent uterine growth in response to E2. Our work has uncovered a novel GPR30-regulated inhibitory event, which may be physiologically relevant in both normal and pathological situations to negatively balance ER alpha-dependent uterine growth regulatory functions induced by E2. (Endocrinology 152: 1434-1447, 2011)