Department of Neuroscience, University of Minnesota, 6-145 Jackson Hall, 321 Church Street, S.E., Minneapolis, MN 55455, USA.
Neuroscience. 2010 Nov 10;170(4):1045-55. doi: 10.1016/j.neuroscience.2010.08.012. Epub 2010 Aug 13.
Along with its ability to directly regulate gene expression, estradiol influences cell signaling and brain functions via rapid, membrane-initiated events. In the female rat striatum, estradiol activates membrane-localized estrogen receptors to influence synaptic neurotransmission, calcium channel activity, and behaviors related to motor control. Yet, the mechanism by which estradiol acts to rapidly affect striatal physiology has remained elusive. Here we find that membrane estrogen receptors (ERs) couple to the metabotropic glutamate receptors mGluR5 and mGluR3, providing the framework to understand how membrane estrogen receptors affect striatal function. Using CREB phosphorylation as a downstream measure of ER/mGluR activation, membrane-localized estrogen receptor α (ERα) activates mGluR5 signaling to mediate mitogen-activated protein kinase (MAPK)-dependent CREB phosphorylation. Further, ERα and estrogen receptor β (ERβ) activate mGluR3 to attenuate L-type calcium channel-dependent CREB signaling. Interestingly, while this fundamental mechanism of ER/mGluR signaling was initially characterized in hippocampal neurons, estrogen receptors in striatal neurons are paired with a different set of mGluRs, resulting in the potential to functionally isolate membrane-initiated estrogen signaling across brain regions via use of specific mGluR modulators. These results provide both a mechanism for the rapid actions of estrogens within the female striatum, as well as demonstrate that estrogen receptors can interact with a more diverse set of surface membrane receptors than previously recognized.
除了能够直接调节基因表达外，雌二醇还通过快速的、膜起始事件影响细胞信号和大脑功能。在雌性大鼠纹状体中，雌二醇激活膜定位的雌激素受体，影响突触神经传递、钙通道活性以及与运动控制相关的行为。然而，雌二醇如何快速影响纹状体生理学的机制仍然难以捉摸。在这里，我们发现膜雌激素受体（ER）与代谢型谷氨酸受体 mGluR5 和 mGluR3 偶联，为理解膜雌激素受体如何影响纹状体功能提供了框架。我们使用 CREB 磷酸化作为 ER/mGluR 激活的下游测量指标，发现膜定位的雌激素受体 α（ERα）激活 mGluR5 信号通路，介导丝裂原活化蛋白激酶（MAPK）依赖性 CREB 磷酸化。此外，ERα 和雌激素受体β（ERβ）激活 mGluR3 以减弱 L 型钙通道依赖性 CREB 信号。有趣的是，虽然这种 ER/mGluR 信号的基本机制最初是在海马神经元中表征的，但纹状体神经元中的雌激素受体与一组不同的 mGluRs 配对，这使得通过使用特定的 mGluR 调节剂在脑区之间功能性分离膜起始的雌激素信号成为可能。这些结果不仅为雌性纹状体中雌激素的快速作用提供了一种机制，还表明雌激素受体可以与比以前认识到的更多样化的表面膜受体相互作用。
