As the new millennium dawned, our understanding of the complexity of estrogenic signaling became much more nuanced, especially in the central nervous system. The first step in the realization that the reception of estradiol signaling was not simple was the cloning of ESR2, the gene that codes for estrogen receptor-b (ERb), which joined ERa as a member of the so-called classical nuclear receptors (Kuiper et al., 1996). Soon thereafter, it was demonstrated that both membrane ERs and nuclear ERs were coded by the same genes that code for the nuclear ERs (Razandi et al., 1999). Dominique Toran-Allerand, who has made many seminal discoveries about ERs, reported that a novel, membrane ER she named ER-X (Toran-Allerand et al., 2002), was present in the cortex during development and re-emerged after injury. This expanded the family of putative membrane ERs to at least three. An orphan G protein-coupled receptor, the GPCR30 also called GPER, was shown to also bind estradiol (Carmeci et al., 1997). A fifth, STX-sensitive putative ER was reported in 2003 (Qiu et al., 2003). These potential receptors have been shown to mediate estradiol signaling throughout the CNS in various circuits. Much has been learned about the cell signaling mechanisms used by these membrane ERs and their regulation of physiology. However the relevance of these putative receptors is still debated, since the majority of evidence indicates that ERa and ERb are critical for most ER-mediated functions. The past 12 years have been very fruitful in demonstrating the necessity of membrane-initiated estradiol signaling in many circuits that previously had been thought of as responding to estradiol through activation of estrogen-response elements (EREs). Now it seems clear that classical ERs can be trafficked to the cell membrane and activate cell signaling cascades that influence circuits responsible for behavior, memory, energy balance, nociception and reproduction. Still, many questions remain. Among them are, what is the mechanism through which membrane ER alter cell signaling? What is the physiological significance of putative membrane ERs apart from ERa and ERb? How does membrane-initiated estradiol signaling interact with ERE-mediated signaling? This special issue of Frontiers in Neuroendocrinology begins to addresses these questions, and raise new ones. Our focus here is on the role of membrane-initiated estradiol signaling in regulating physiological processes and behavior. Micevych and Christensen examine the proximal signaling of the mER and review evidence that this signaling requires an interaction of ERa-mGluR interactions, which have been demonstrated throughout the nervous system in both neurons and astrocytes (Micevych and Christensen, 2012). They discuss the membrane ERa mediated actions on neuronal morphology, sexual receptivity and neuroprogesterone syn-

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膜启动的雌二醇信号调节中枢神经系统

随着新千年的到来，我们对雌激素信号复杂性的理解变得更加微妙，尤其是在中枢神经系统中。认识到接受雌二醇信号并不简单的第一步是克隆 ESR2，即编码雌激素受体 b (ERb) 的基因，它作为所谓的经典核受体 (Kuiper) 的成员加入了 ERa等人，1996 年）。此后不久，证明膜内质网和核内质网均由编码核内质网的相同基因编码（Razandi 等，1999）。多米尼克·托兰·阿莱兰 (Dominique Toran-Allerand) 对内质网做出了许多开创性的发现，她报告称，一种她命名为 ER-X 的新型膜内质网 (Toran-Allerand et al., 2002)，在发育过程中出现在皮层中，并在受伤后重新出现. 这将假定的膜 ER 家族扩展到至少三个。孤儿 G 蛋白偶联受体 GPCR30 也称为 GPER，显示也能结合雌二醇（Carmeci 等，1997）。2003 年报道了第五个 STX 敏感的推定 ER（Qiu 等，2003）。这些潜在的受体已被证明可以在各种回路中介导整个中枢神经系统的雌二醇信号传导。关于这些膜 ER 使用的细胞信号机制及其对生理学的调节，已经了解了很多。然而，这些假定受体的相关性仍然存在争议，因为大多数证据表明 ERα 和 ERβ 对大多数 ER 介导的功能至关重要。过去 12 年在证明膜启动的雌二醇信号传导在许多回路中的必要性方面取得了丰硕成果，这些回路以前被认为是通过激活雌激素反应元件 (ERE) 对雌二醇作出反应。现在似乎很清楚，经典的 ER 可以运输到细胞膜并激活细胞信号级联，影响负责行为、记忆、能量平衡、伤害感受和繁殖的电路。尽管如此，仍有许多问题。其中，膜内质网改变细胞信号的机制是什么？除 ERa 和 ERb 外，推定的膜 ER 的生理意义是什么？膜启动的雌二醇信号如何与 ERE 介导的信号相互作用？本期《神经内分泌学前沿》特刊开始解决这些问题，并培养新的。我们在这里的重点是膜启动的雌二醇信号在调节生理过程和行为中的作用。Micevych 和 Christensen 检查了 mER 的近端信号，并审查了该信号需要 ERa-mGluR 相互作用的证据，这已在神经元和星形胶质细胞的整个神经系统中得到证明（Micevych 和 Christensen，2012）。他们讨论了膜 ERa 介导的对神经元形态、性接受能力和神经孕酮合成的作用。这已在神经元和星形胶质细胞的整个神经系统中得到证实（Micevych 和 Christensen，2012 年）。他们讨论了膜 ERa 介导的对神经元形态、性接受能力和神经孕酮合成的作用。这已在神经元和星形胶质细胞的整个神经系统中得到证实（Micevych 和 Christensen，2012 年）。他们讨论了膜 ERa 介导的对神经元形态、性接受能力和神经孕酮合成的作用。