Boulware Marissa I, Kordasiewicz Holly, Mermelstein Paul G
Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, USA.
J Neurosci. 2007 Sep 12;27(37):9941-50. doi: 10.1523/JNEUROSCI.1647-07.2007.
It has become widely accepted that along with its ability to directly regulate gene expression, estradiol also influences cell signaling and brain function via rapid membrane-initiated events. Many of these novel signaling processes are dependent on estrogen receptors (ERs) localized to the neuronal membrane. However, the mechanism(s) by which ERs are able to trigger cell signaling when targeted to the neuronal membrane surface has yet to be determined. In hippocampal neurons, we find that caveolin proteins are essential for the regulation of CREB (cAMP response element-binding protein) phosphorylation after estradiol activation of metabotropic glutamate receptor (mGluR) signaling. Furthermore, caveolin-1 (CAV1) and CAV3 differentially regulate the ability of estradiol to activate two discrete signaling pathways. ER alpha activation of mGluR1a is dependent on CAV1, whereas CAV3 is necessary for ER alpha and ER beta activation of mGluR2/3. These results are consistent with previous reports in non-neuronal cells, implicating the importance of caveolin proteins in rapid estrogen signaling. In addition, the functional isolation of distinct estrogen-sensitive signaling pathways by different caveolin proteins suggests novel mechanisms through which the membrane-initiated effects of estradiol are orchestrated.
人们已经广泛接受，除了直接调节基因表达的能力外，雌二醇还通过快速的膜起始事件影响细胞信号传导和脑功能。许多这些新的信号传导过程依赖于定位于神经元膜的雌激素受体（ERs）。然而，当ERs靶向神经元膜表面时能够触发细胞信号传导的机制尚未确定。在海马神经元中，我们发现小窝蛋白对于代谢型谷氨酸受体（mGluR）信号经雌二醇激活后CREB（cAMP反应元件结合蛋白）磷酸化的调节至关重要。此外，小窝蛋白-1（CAV1）和小窝蛋白-3（CAV3）对雌二醇激活两条不同信号通路的能力有不同调节作用。mGluR1a的ERα激活依赖于CAV1，而CAV3是ERα和ERβ激活mGluR2/3所必需的。这些结果与之前在非神经元细胞中的报道一致，表明小窝蛋白在快速雌激素信号传导中的重要性。此外，不同的小窝蛋白对不同雌激素敏感信号通路的功能分离提示了协调雌二醇膜起始效应的新机制。
