Department of Physiological Sciences, University of Florida, Gainesville, FL, 32610, USA.
Department of Physiological Sciences, University of Florida, Gainesville, FL, 32610, USA.
Differentiation. 2021 Mar-Apr;118:24-33. doi: 10.1016/j.diff.2020.11.002. Epub 2020 Dec 9.
Estrogen signaling through the main estrogen receptor, estrogen receptor 1 (ESR1; also known as ERα), is essential for normal female and male reproductive function. Historically, studies of estrogen action have focused on the classical genomic pathway. Although this is clearly the major pathway for steroid hormone actions, these hormones also signal through rapid non-classical effects involving cell membrane actions. Reports of rapid effects of estrogens extend for more than half a century, but recent results have expanded understanding of the identity, structure, function and overall importance of membrane receptors in estrogen responses. Key findings in this field were the immunohistochemical detection of ESR1 in cell membranes and demonstration that a portion of newly synthesized ESR1 is routed to the membrane by palmitoylation. These receptors in the membrane can then signal through protein kinases and other mechanisms following ligand binding to alter cell function. Another crucial advance in the field was development of transgenic mice expressing normal amounts of functional nuclear ESR1 (nESR1) but lacking membrane ESR1 (mESR1). Both male and female transgenic mice lacking mESR1 were infertile as adults, and both sexes had extensive reproductive abnormalities. Transgenic mice lacking mESR1 were highly protected from deleterious effects of neonatal estrogen administration, and estrogen effects on the histone methyltransferase Enhancer of Zeste homolog 2 that are mediated through mESR1 could have significant effects on epigenetic imprinting. In summary, signaling through mESR1 is essential for normal male and female reproductive function and fertility, and is a critical enabler of normal estrogen responses in vivo. Although the precise role of mESR1 in estrogen responses remains to be established, future research in this area should clarify its mechanism of action and lead to a better understanding of how mESR1 signaling works with classical genomic signaling through nESR1 to promote full estrogenic responses.
雌激素通过主要雌激素受体（雌激素受体 1，ESR1；也称为 ERα）发挥信号作用，对于正常的女性和男性生殖功能至关重要。从历史上看，对雌激素作用的研究主要集中在经典的基因组途径上。尽管这显然是甾体激素作用的主要途径，但这些激素也通过涉及细胞膜作用的快速非经典作用来发挥信号作用。雌激素快速作用的报告已经有半个多世纪的历史，但最近的结果扩展了对膜受体在雌激素反应中的身份、结构、功能和整体重要性的理解。该领域的关键发现是在细胞膜中检测到 ESR1 的免疫组织化学，并证明一部分新合成的 ESR1 通过棕榈酰化被定向到膜。结合配体后，这些膜中的受体可以通过蛋白激酶和其他机制发出信号，从而改变细胞功能。该领域的另一个重要进展是开发出表达正常数量功能性核雌激素受体 1（nESR1）但缺乏膜雌激素受体 1（mESR1）的转基因小鼠。缺乏 mESR1 的雄性和雌性转基因小鼠成年后均不育，且两性均有广泛的生殖异常。缺乏 mESR1 的转基因小鼠对新生期雌激素给药的有害作用具有高度保护作用，而 mESR1 介导的雌激素对组蛋白甲基转移酶 Enhancer of Zeste homolog 2 的作用可能对表观遗传印记产生重大影响。总之，mESR1 的信号作用对于正常的男性和女性生殖功能和生育能力至关重要，是体内正常雌激素反应的关键促成因素。虽然 mESR1 在雌激素反应中的确切作用仍有待确定，但该领域的未来研究应阐明其作用机制，并更好地了解 mESR1 信号如何与通过 nESR1 的经典基因组信号协同作用，以促进充分的雌激素反应。
