Cardona-Gomez P, Perez M, Avila J, Garcia-Segura L M, Wandosell F
Centro de Biología Molecular Severo Ochoa CSIC-Universidad Autónoma de Madrid, Madrid 28049, Spain.
Mol Cell Neurosci. 2004 Mar;25(3):363-73. doi: 10.1016/j.mcn.2003.10.008.
Estrogens regulate a wide set of neuronal functions such as gene expression, survival and differentiation in a manner not very different from that exerted by neurotrophins or by growth factors. The best-studied hormonal action is the transcriptional activation mediated by estrogen receptors. However, the direct effects of estrogen on growth factor signaling have not been well clarified. The present data show that estradiol, in vivo, induces a transient activation of GSK3 in the adult female rat hippocampus, followed by a more sustained inhibition, as inferred from phosphorylation levels of Tau. Similar data was obtained from cultured hippocampal neurons when treated with the hormone. The transient activation was confirmed by direct measure of GSK3 kinase activity. In addition, our results show a novel complex of estrogen receptor alpha, GSK3, and beta-catenin. The presence of the hormone removes beta-catenin from this complex. There is a second complex, also affected by estradiol, in which Tau is associated with GSK3, beta-catenin, and elements of the PI3 kinase complex. Considering the role of GSK3 in neurodegeneration, our data suggest that part of the neuroprotective effects of estrogen may be due to the control of GSK3.
雌激素以一种与神经营养因子或生长因子所发挥的作用并无太大差异的方式，调节着一系列广泛的神经元功能，如基因表达、存活和分化。研究最为深入的激素作用是由雌激素受体介导的转录激活。然而，雌激素对生长因子信号传导的直接影响尚未得到充分阐明。目前的数据表明，在成年雌性大鼠海马体中，雌二醇在体内会诱导糖原合成酶激酶3（GSK3）的短暂激活，随后从微管相关蛋白Tau的磷酸化水平推断，会出现更持久的抑制。在用该激素处理培养的海马神经元时，也获得了类似的数据。通过直接测量GSK3激酶活性证实了短暂激活。此外，我们的结果显示了一种由雌激素受体α、GSK3和β-连环蛋白组成的新型复合物。激素的存在会使β-连环蛋白从该复合物中脱离。还有第二种复合物，也受雌二醇影响，其中Tau与GSK3、β-连环蛋白以及磷脂酰肌醇-3激酶（PI3激酶）复合物的成分相关联。考虑到GSK3在神经退行性变中的作用，我们的数据表明雌激素的部分神经保护作用可能归因于对GSK3的调控。
