Effects of progesterone and its reduced metabolites, dihydroprogesterone and tetrahydroprogesterone, on the expression and phosphorylation of glycogen synthase kinase-3 and the microtubule-associated protein Tau in the rat cerebellum
Effects of progesterone and its reduced metabolites, dihydroprogesterone and tetrahydroprogesterone, on the expression and phosphorylation of glycogen synthase kinase-3 and the microtubule-associated protein Tau in the rat cerebellum
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DOI：
10.1002/dneu.20383
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发表时间：
2007-03-01
影响因子：
3
通讯作者：
Garcia-Segura, Luis M.
中科院分区：
文献类型：
--
作者：
Guerra-Araiza, Christian;Amorim, Miguel A. R.;Garcia-Segura, Luis M.
孕酮在大脑中发挥各种作用，在大脑中快速代谢为5 α-二氢孕酮（DHP）和3 α，5 α-四氢孕酮（THP）。孕酮及其代谢物对微管相关蛋白Tau和糖原合成酶激酶3 β（GSK 3 β）（一种参与Tau磷酸化的激酶）的表达和磷酸化的影响在两个对孕酮敏感的脑区进行了评估：下丘脑和小脑。给予孕酮，DHP，和THP卵巢切除大鼠不影响Tau和GSK 3 β在整个下丘脑匀浆评估。相反，孕酮及其代谢产物导致小脑中Tau和GSK 3 β的表达显著降低。此外，孕酮给药导致被GSK 3 β磷酸化的Tau的两个表位（Tau-1和PHF-1）的磷酸化增加，但不影响GSK 3 β不敏感的Tau的表位（Ser 262）的磷酸化。这些作用伴随着丝氨酸中GSK 3 β磷酸化的减少，这与其活性的增加相关，表明孕酮对小脑中Tau-1和PHF-1磷酸化的作用是由GSK 3 β介导的。孕激素对Tau蛋白表达和磷酸化的调节可能通过修饰神经元细胞骨架而参与了小脑功能的激素调节。(c)2007 Wiley Periodicals，Inc.
Progesterone exerts a variety of actions in the brain, where it is rapidly metabolized to 5ot-dihydroprogesterone (DHP) and 3 alpha,5 alpha-tetrahydroprogesterone (THP). The effect of progesterone and its metabolites on the expression and phosphorylation of the microtubule-associated protein Tau and glycogen synthase kinase 3 beta (GSK3 beta), a kinase involved in Tau phosphorylation, were assessed in two progesterone-sensitive brain areas: the hypothalamus and the cerebellum. Administration of progesterone, DHP, and THP to ovariectornized rats did not affect Tau and GSK3 beta assessed in whole hypothalamic homogenates. In contrast, progesterone and its metabolites resulted in a significant decrease in the expression of Tau and GSK3 beta in the cerebellum. Furthermore, progesterone administration resulted in an increase in the phosphorylation of two epitopes of Tau (Tau-1 and PHF-1) phosphorylated by GSK3 beta, but did not affect the phosphorylation of an epitope of Tau (Ser262) that is GSK3 beta insensitive. These effects were accompanied by a decrease in the phosphorylation of GSK3 beta in serine, which is associated to an increase in its activity, suggesting that the effect of progesterone on Tau-1 and PHF-1 phosphorylation in the cerebellum is mediated by GSK3 beta. The regulation of Tau expression and phosphorylation by progesterone may contribute to the hormonal regulation of cerebellar function by the modification of neuronal cytoskeleton. (c) 2007 Wiley Periodicals, Inc.