Estrogens are critical mediators of multiple and diverse physiologic effects throughout the body in both sexes, including the reproductive, cardiovascular, endocrine, nervous, and immune systems. As such, alterations in estrogen function play important roles in many diseases and pathophysiological conditions (including cancer), exemplified by the lower prevalence of many diseases in premenopausal women. Estrogens mediate their effects through multiple cellular receptors, including the nuclear receptor family (ERα and ERβ) and the G protein-coupled receptor (GPCR) family (GPR30/G protein-coupled estrogen receptor [GPER]). Although both receptor families can initiate rapid cell signaling and transcriptional regulation, the nuclear receptors are traditionally associated with regulating gene expression, whereas GPCRs are recognized as mediating rapid cellular signaling. Estrogen-activated pathways are not only the target of multiple therapeutic agents (e.g., tamoxifen, fulvestrant, raloxifene, and aromatase inhibitors) but are also affected by a plethora of phyto- and xeno-estrogens (e.g., genistein, coumestrol, bisphenol A, dichlorodiphenyltrichloroethane). Because of the existence of multiple estrogen receptors with overlapping ligand specificities, expression patterns, and signaling pathways, the roles of the individual receptors with respect to the diverse array of endogenous and exogenous ligands have been challenging to ascertain. The identification of GPER-selective ligands however has led to a much greater understanding of the roles of this receptor in normal physiology and disease as well as its interactions with the classic estrogen receptors ERα and ERβ and their signaling pathways. In this review, we describe the history and characterization of GPER over the past 15 years focusing on the pharmacology of steroidal and nonsteroidal compounds that have been employed to unravel the biology of this most recently recognized estrogen receptor.

中文翻译：

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国际基础与临床药理学联盟。XCVII. G 蛋白偶联雌激素受体及其药理调节剂。

雌激素是两性体内多种不同生理效应的关键介质，包括生殖、心血管、内分泌、神经和免疫系统。因此，雌激素功能的改变在许多疾病和病理生理状况（包括癌症）中发挥着重要作用，绝经前妇女中许多疾病的患病率较低就是例证。雌激素通过多种细胞受体介导其作用，包括核受体家族（ERα和ERβ）和G蛋白偶联受体（GPCR）家族（GPR30/G蛋白偶联雌激素受体[GPER]）。尽管两个受体家族都可以启动快速细胞信号传导和转录调节，但核受体传统上与调节基因表达有关，而 GPCR 被认为介导快速细胞信号传导。雌激素激活途径不仅是多种治疗药物（例如他莫昔芬、氟维司群、雷洛昔芬和芳香酶抑制剂）的靶标，而且还受到大量植物雌激素和异种雌激素（例如金雀花素、香豆雌酚、双酚 A、二氯二苯基三氯乙烷）。由于存在具有重叠配体特异性、表达模式和信号通路的多种雌激素受体，因此单个受体相对于多种内源性和外源性配体的作用一直难以确定。然而，GPER 选择性配体的鉴定使人们对该受体在正常生理和疾病中的作用以及其与经典雌激素受体 ERα 和 ERβ 的相互作用及其信号通路有了更深入的了解。在这篇综述中，我们描述了过去 15 年 GPER 的历史和特征，重点关注甾体和非甾体化合物的药理学，这些化合物已被用来阐明这种最近公认的雌激素受体的生物学特性。