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首页> 外文期刊>Frontiers in neuroendocrinology >Novel mechanisms of estrogen action in the brain: new players in an old story.
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Novel mechanisms of estrogen action in the brain: new players in an old story.

机译：大脑中雌激素作用的新机制：旧故事中的新参与者。

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Estrogen elicits a selective enhancement of the growth and differentiation of axons and dendrites (neurites) in the developing brain. Widespread colocalization of estrogen and neurotrophin receptors (trk) within estrogen and neurotrophin targets, including neurons of the cerebral cortex, sensory ganglia, and PC12 cells, has been shown to result in differential and reciprocal transcriptional regulation of these receptors by their ligands. In addition, estrogen and neurotrophin receptor coexpression leads to convergence or cross-coupling of their signaling pathways, particularly at the level of the mitogen-activated protein (MAP) kinase cascade. 17beta-Estradiol elicits rapid (within 5-15 min) and sustained (at least 2 h) tyrosine phosphorylation and activation of the MAP kinases, extracellular-signal regulated kinase (ERK)1, and ERK2, which is successfully inhibited by the MAP kinase/ERK kinase 1 inhibitor PD98059, but not by the estrogen receptor (ER) antagonist ICI 182,780 and also does not appear to result from estradiol-induced activation of trk. Furthermore, the ability of estradiol to phosphorylate ERK persists even in ER-alpha knockout mice, implicating other estrogen receptors such as ER-beta in these actions of estradiol. The existence of an estrogen receptor-containing, multimeric complex consisting of hsp90, src, and B-Raf also suggests a direct link between the estrogen receptor and the MAP kinase signaling cascade. Collectively, these novel findings, coupled with our growing understanding of additional signaling substrates utilized by estrogen, provide alternative mechanisms for estrogen action in the developing brain which could explain not only some of the very rapid effects of estrogen, but also the ability of estrogen and neurotrophins to regulate the same broad array of cytoskeletal and growth-associated genes involved in neurite growth and differentiation. This review expands the usually restrictive view of estrogen action in the brain beyond the confines of sexual differentiation and reproductive neuroendocrine function. It considers the much broader question of estrogen as a neural growth factor with important influences on the development, survival, plasticity, regeneration, and aging of the mammalian brain and supports the view that the estrogen receptor is not only a ligand-induced transcriptional enhancer but also a mediator of rapid, nongenomic events. Copyright 1999 Academic Press.
机译：雌激素引起发展中的大脑中轴突和树突（神经突）的生长和分化的选择性增强。在雌激素和神经营养蛋白靶标（包括大脑皮层，感觉神经节和PC12细胞的神经元）内，雌激素和神经营养蛋白受体（trk）的广泛共定位已显示可导致这些受体的配体发生差异性和相互的转录调控。另外，雌激素和神经营养蛋白受体的共表达导致它们的信号传导途径趋同或交叉耦合，特别是在促分裂原活化蛋白（MAP）激酶级联反应的水平上。 17beta-雌二醇引起快速（5-15分钟内）和持续（至少2小时）酪氨酸磷酸化以及MAP激酶，细胞外信号调节激酶（ERK）1和ERK2的激活，而MAP激酶成功地抑制了它们/ ERK激酶1抑制剂PD98059，但不是雌激素受体（ER）拮抗剂ICI 182,780，也似乎不是由雌二醇诱导的trk活化引起的。此外，雌二醇使ERK磷酸化的能力甚至在ER-α基因敲除小鼠中也持续存在，这与其他雌激素受体（例如ER-β）有关。由hsp90，src和B-Raf组成的含雌激素受体的多聚体复合物的存在也暗示了雌激素受体与MAP激酶信号级联反应之间的直接联系。总的来说，这些新颖的发现，加上我们对雌激素所利用的其他信号传递底物的日益了解，为发育中的大脑提供了雌激素作用的替代机制，这不仅可以解释雌激素的某些非常迅速的作用，而且可以解释雌激素的能力。神经营养蛋白可调节与神经突生长和分化有关的细胞骨架和与生长相关的基因。这篇综述扩大了对大脑中雌激素作用的通常限制性观点，超越了性别分化和生殖神经内分泌功能的范围。它认为雌激素是一个神经生长因子，它对哺乳动物大脑的发育，存活，可塑性，再生和衰老具有重要影响，是一个更为广泛的问题，并支持以下观点：雌激素受体不仅是配体诱导的转录增强子，而且还是非基因组快速事件的调解人。版权所有1999 Academic Press。

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