Dept. of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA.
J Chem Neuroanat. 2011 Dec;42(4):236-41. doi: 10.1016/j.jchemneu.2011.02.002. Epub 2011 Mar 31.
Estradiol and other steroid hormones modulate the nervous system and behavior on both acute and long-term time scales. Though estradiol was originally characterized as a regulator of gene expression through the action of nuclear estrogen receptors (ERs) that directly bind DNA, research over the past thirty years has firmly established that estradiol can bind to extra-nuclear ERs associated with the cellular membrane, producing changes in neurons through stimulation of various intracellular signaling pathways. Several studies have determined that the classical ERs, ERα and ERβ, mediate some of these fast-acting signaling pathways through activation of G proteins. Since ERα and ERβ are not G protein-coupled receptors, the mechanisms by which ERs can stimulate signal transduction pathways are a focus of recent research. Here we discuss recent studies illustrating one mechanism by which ERα and ERβ initiate these pathways: through direct association with metabotropic glutamate receptors (mGluRs). Estradiol binding to these membrane-localized estrogen receptors results in mGluR signaling independent of glutamate. ERs are organized with mGluRs into functional signaling microdomains via caveolin proteins. The pairing of ERs to specific mGluRs via caveolins is region specific, with ERs being linked to different mGluRs in hippocampal, striatal, and other neurons. It is becoming clear that ER signaling through mGluRs is one important mechanism by which estrogens can modulate neuron and glial physiology, ultimately impacting various aspects of nervous system function.
雌二醇和其他甾体激素在急性和长期时间尺度上调节神经系统和行为。尽管雌二醇最初被描述为通过与 DNA 直接结合的核雌激素受体 (ER) 作用调节基因表达的调节剂，但过去三十年的研究已经明确确立，雌二醇可以与与细胞膜相关的核外 ER 结合，通过刺激各种细胞内信号通路来改变神经元。几项研究已经确定，经典的 ER，即 ERα 和 ERβ，通过激活 G 蛋白介导其中一些快速作用的信号通路。由于 ERα 和 ERβ 不是 G 蛋白偶联受体，因此 ER 刺激信号转导通路的机制是最近研究的重点。在这里，我们讨论了最近的研究，这些研究说明了 ERα 和 ERβ 启动这些通路的一种机制：通过与代谢型谷氨酸受体 (mGluR) 的直接结合。雌二醇与这些膜定位的雌激素受体结合会导致独立于谷氨酸的 mGluR 信号。ER 与 mGluR 通过 caveolin 蛋白形成功能性信号微区。通过 caveolins 将 ER 与特定的 mGluR 配对是区域特异性的，在海马体、纹状体和其他神经元中，ER 与不同的 mGluR 相关联。越来越明显的是，通过 mGluR 的 ER 信号是雌激素调节神经元和神经胶质生理学的一种重要机制，最终影响神经系统功能的各个方面。
