Abrahám István M, Todman Martin G, Korach Kenneth S, Herbison Allan E
Laboratory of Neuroendocrinology, Babraham Institute, Cambridge, United Kingdom.
Endocrinology. 2004 Jul;145(7):3055-61. doi: 10.1210/en.2003-1676. Epub 2004 Feb 19.
Estrogen exerts classical genomic as well as rapid nongenomic actions on neurons. The mechanisms involved in rapid estrogen signaling are poorly defined, and the roles of the classical estrogen receptors (ERs alpha and beta) are unclear. We examined here the in vivo role of classical ERs in rapid estrogen actions by evaluating the estrogen-induced effects on two major signaling pathways within the brains of alphaER-, betaER-, and double alphabetaER-knockout (ERKO) ovariectomized female mice. Estrogen significantly (P < 0.05) increased the numbers of phospho-cAMP response element binding protein (phospho-CREB)-immunoreactive cells in specific brain regions of wild-type mice in a time-dependent manner beginning within 15 min. In brain areas that express predominantly ERbeta, this response was absent in betaERKO mice, whereas brain regions that express mostly ERalpha displayed no change in alphaERKO mice. In the medial preoptic nucleus (MPN), an area that expresses both ERs, the estrogen-induced phosphorylation of CREB was normal in both alphaERKO and betaERKO mice. However, estrogen had no effect on CREB phosphorylation in the MPN, or any other brain region, in double alphabetaERKO animals. Estrogen was also found to increase MAPK phosphorylation levels in a rapid (<15 min) manner within the MPN. In contrast to CREB signaling, this effect was lost in either alphaERKO or betaERKO mice. These data show that ERalpha and ERbeta play region- and pathway-specific roles in rapid estrogen actions throughout the brain. They further indicate an indispensable role for classical ERs in rapid estrogen actions in vivo and highlight the importance of ERs in coordinating both classical and rapid actions of estrogen.
雌激素对神经元发挥经典的基因组作用以及快速的非基因组作用。快速雌激素信号传导所涉及的机制尚不明确，经典雌激素受体（α型和β型雌激素受体）的作用也不清楚。我们在此通过评估雌激素对α型雌激素受体、β型雌激素受体和αβ型雌激素受体双敲除（ERKO）去卵巢雌性小鼠脑内两条主要信号通路的诱导作用，研究经典雌激素受体在雌激素快速作用中的体内作用。雌激素显著（P < 0.05）增加野生型小鼠特定脑区中磷酸化环磷酸腺苷反应元件结合蛋白（磷酸化-CREB）免疫反应性细胞的数量，从15分钟内开始呈时间依赖性。在主要表达β型雌激素受体的脑区，β型雌激素受体敲除小鼠中没有这种反应，而主要表达α型雌激素受体的脑区在α型雌激素受体敲除小鼠中没有变化。在内侧视前核（MPN），一个同时表达两种雌激素受体的区域，α型雌激素受体敲除小鼠和β型雌激素受体敲除小鼠中雌激素诱导的CREB磷酸化均正常。然而，在αβ型雌激素受体双敲除动物中，雌激素对MPN或任何其他脑区的CREB磷酸化没有影响。还发现雌激素能在MPN内快速（<15分钟）增加丝裂原活化蛋白激酶（MAPK）的磷酸化水平。与CREB信号传导不同，这种作用在α型雌激素受体敲除或β型雌激素受体敲除小鼠中均消失。这些数据表明，α型雌激素受体和β型雌激素受体在全脑雌激素快速作用中发挥区域和通路特异性作用。它们进一步表明经典雌激素受体在体内雌激素快速作用中不可或缺，并突出了雌激素受体在协调雌激素经典作用和快速作用方面的重要性。
