Cross D A, Culbert A A, Chalmers K A, Facci L, Skaper S D, Reith A D
Neurology Centre of Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, Harlow, Essex, UK.
J Neurochem. 2001 Apr;77(1):94-102. doi: 10.1046/j.1471-4159.2001.t01-1-00251.x.
The phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B (PKB; also known as Akt) signalling pathway is recognized as playing a central role in the survival of diverse cell types. Glycogen synthase kinase-3 (GSK-3) is a 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.
磷脂酰肌醇3激酶（PI 3激酶）/蛋白激酶B（PKB；也称为Akt）信号通路在多种细胞类型的存活中起着核心作用。糖原合酶激酶3（GSK - 3）是一种广泛表达的丝氨酸/苏氨酸蛋白激酶，是PKB已知的几种底物之一。PKB在胰岛素和生长因子的作用下使GSK - 3磷酸化，这会抑制GSK - 3的活性，并导致对多种受GSK - 3调节的细胞过程的调控。我们发现新型强效且选择性的GSK - 3小分子抑制剂SB - 415286和SB - 216763，可保护培养中的中枢和外周神经系统神经元免受因PI 3激酶途径活性降低所诱导的死亡。这些化合物介导的对神经元死亡的抑制与GSK - 3活性的抑制以及GSK - 3底物tau和β - 连环蛋白的调控相关。因此，除了GSK - 3先前已确定的作用外，我们的数据提供了明确的药理学和生物化学证据，即对原代神经元中内源性GSK - 3活性的选择性抑制足以防止细胞死亡，这表明GSK - 3是PI 3激酶/PKB神经元存活途径中生理上相关的主要调节靶点。
