Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from death
Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from death
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DOI：
10.1046/j.1471-4159.2001.t01-1-00251.x
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发表时间：
2001-04-01
影响因子：
4.7
通讯作者：
Reith, AD
中科院分区：
文献类型：
--
作者：
Cross, DAE;Culbert, AA;Reith, AD
磷脂酰肌醇3-激酶（PI 3-kinase）/蛋白激酶B（PK B;也称为AM）信号传导途径被认为在不同细胞类型的存活中起核心作用。糖原合成酶激酶-3（Glycogen synthase kinase-3，GSK-3）伊萨一种广泛表达的丝氨酸/苏氨酸蛋白激酶，是蛋白激酶B的底物之一。PKB磷酸化; GSK-3响应胰岛素和生长因子，其抑制GSK-3活性并导致多种GSK-3调节的细胞过程的调节。我们发现，GSK-3的新型强效和选择性小分子抑制剂SB-415286和SB-216763，保护培养的中枢和外周神经系统神经元免于PI 3-激酶途径活性降低诱导的死亡。由这些化合物介导的神经元死亡的抑制与GSK-3活性的抑制和GSK-3底物tau和β-连环蛋白的调节相关。因此，除了先前分配的GSK-3的作用，我们的数据提供了明确的药理学和生化证据，选择性抑制原发神经元中GSK-3活性的内源性池足以防止死亡，暗示GSK-3作为PI 3-激酶/PKB神经元存活途径的生理相关的主要调节靶点。
The phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B (PKB; also known as AM) signalling pathway is recognized as playing a central role in the survival of diverse cell types. Glycogen synthase kinase-3 (GSK-3) isa ubiquitously expressed serine/threonine protein kinase that is one of several known substrates of PKB. PKB phosphorylates; GSK-3 in response to insulin and growth factors, which inhibits GSK-3 activity and leads to the modulation of multiple GSK-3 regulated cellular processes. We show that the novel potent and selective small-molecule inhibitors of GSK-3; SB-415286 and SB-216763, protect both central and peripheral nervous system neurones in culture from death induced by reduced PI 3-kinase pathway activity. The inhibition of neuronal death mediated by these compounds correlated with inhibition of GSK-3 activity and modulation of GSK-3 substrates tau and beta -catenin. Thus, in addition to the previously assigned roles of GSK-3, our data provide clear pharmacological and biochemical evidence that selective inhibition of the endogenous pool of GSK-3 activity in primary neurones is sufficient to prevent death, implicating GSK-3 as a physiologically relevant principal regulatory target of the PI 3-kinase/PKB neuronal survival pathway.