EP2 Receptor Activates Dual G Protein Signaling Pathways that Mediate Contrasting Proinflammatory and Relaxatory Responses in Term Pregnant Human Myometrium
EP2 Receptor Activates Dual G Protein Signaling Pathways that Mediate Contrasting Proinflammatory and Relaxatory Responses in Term Pregnant Human Myometrium
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DOI：
10.1210/en.2013-1761
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发表时间：
2014-02-01
期刊：
影响因子：
4.8
通讯作者：
Bennett, Phillip R.
中科院分区：
文献类型：
--
作者：
Kandola, Mandeep K.;Sykes, Lynne;Bennett, Phillip R.
前列腺素（PG） E2 （PGE(2)）在平滑肌收缩的调节中起核心作用。典型地，PGE(2)通过EP1和EP3受体刺激收缩，而EP2和EP4保持静止。产程包括从肌层静止到收缩的变化，从抗炎途径转变为促炎途径。EP2是一种G α s偶联受体，已知通过cAMP信号传导介导其作用。然而，我们最近发现EP2也能激活促炎的PG G/H合成酶-2 （PGHS-2）。在这里，我们确定了EP2维持子宫静止和激活足月妊娠人子宫肌层促炎/促产程反应能力的机制。人子宫肌瘤活检进行体内和体外研究在剖宫产在足月，分娩之前或之后开始。EP2的激活增加了细胞内cAMP水平并降低了收缩性。相比之下，EP2刺激增加了PGHS-2、膜相关PGE合成酶-1和PGE的水平(2)。这完全依赖于ep2介导的钙信号激活。钙信号和PGHS-2的上调均对G α i抑制剂百日咳毒素不敏感，但被G α q/11的小干扰RNA敲低抑制。EP2mRNAor蛋白水平在上节段和下节段肌层之间、分娩前后肌层之间均无差异。然而，在分娩开始后采集的肌细胞中，cAMP信号明显减弱，而钙和PGHS-2的激活得以保留。总的来说，EP2与G α s-cAMP和G α q/11-钙通路的双重偶联是其在足月妊娠和向分娩前受体“转换”中调节不同功能的能力的基础。
Prostaglandin (PG) E2 (PGE(2)) plays a central role in the regulation of smooth muscle contractions. Classically, PGE(2) stimulates contractions via EP1 and EP3 receptors, whereas EP2 and EP4 maintain quiescence. Labor involves a change from myometrial quiescence to contractions with a shift from anti-to proinflammatory pathways. EP2, a G alpha s-coupled receptor, is known to mediate its actions via cAMP signaling. However, we have recently shown that EP2 also activates the proinflammatory PG G/H synthase-2 (PGHS-2). Here, we identify the mechanism underlying the ability of EP2 to maintain uterine quiescence and activate a proinflammatory/prolabor response in term-pregnant human myometrium. Human myometrial biopsies for in vivo and in vitro studies were taken at cesarean section at term, before or after the onset of labor. Activation of EP2 increased intracellular levels of cAMP and reduced contractility. Contrastingly, EP2 stimulation increased levels of PGHS-2, membrane-associated PGE synthase-1, and PGE(2). This was entirely dependent on EP2-mediated activation of calcium signaling. Both calcium signaling and up-regulation of PGHS-2 were insensitive to the G alpha i inhibitor pertussis toxin but inhibited by small interfering RNA knockdown of G alpha q/11. There were no differences in EP2mRNAor protein levels between upper or lower segment myometrium or between pre- and postlabor myometrium. However, in myocytes taken after the onset of labor, cAMP signaling was markedly attenuated, whereas activation of calcium and PGHS-2 was preserved. Overall, the dual coupling of EP2 to G alpha s-cAMP and G alpha q/11-calcium pathways underlies its ability to mediate contrasting functions in term pregnancy and the "switching" to a prolabor receptor.