Department of Biochemistry, Veterinary Faculty, Complutense University of Madrid, Madrid, Spain.
Cell Mol Life Sci. 2010 May;67(10):1723-33. doi: 10.1007/s00018-010-0278-x. Epub 2010 Feb 10.
Glycogen synthase kinase-3 (GSK3) is a key player in the regulation of neuronal survival. Herein, we report evidence of an interaction between P2X7 receptors with NMDA and BDNF receptors at the level of GSK3 signalling and neuroprotection. The activation of these receptors in granule neurons led to a sustained pattern of GSK3 phosphorylation that was mainly PKC-dependent. BDNF was the most potent at inducing GSK3 phosphorylation, which was also dependent on PI3K. The P2X7 agonist, BzATP, exhibited additive effects with both NMDA and BDNF to rescue granule neurons from cell death induced by PI3K inhibition. This survival effect was mediated by the PKC-dependent GSK3 pathway. In addition, ERK1/2 proteins were also involved in BDNF protective effect. These results show the function of ATP in amplifying neuroprotective actions of glutamate and neurotrophins, and support the role of GSK3 as an important convergence point for these survival promoting factors in granule neurons.
糖原合酶激酶-3（GSK3）是神经元存活调节中的关键因子。在此，我们报告了 P2X7 受体与 NMDA 和 BDNF 受体在 GSK3 信号转导和神经保护水平上相互作用的证据。这些受体在颗粒神经元中的激活导致了 GSK3 磷酸化的持续模式，主要依赖于蛋白激酶 C（PKC）。BDNF 是诱导 GSK3 磷酸化最有效的物质，这也依赖于磷酸肌醇 3-激酶（PI3K）。P2X7 激动剂 BzATP 与 NMDA 和 BDNF 均具有相加作用，可挽救因 PI3K 抑制而导致的颗粒神经元死亡。这种存活效应是通过 PKC 依赖性 GSK3 途径介导的。此外，细胞外信号调节激酶 1/2（ERK1/2）蛋白也参与了 BDNF 的保护作用。这些结果表明了 ATP 在放大谷氨酸和神经营养因子的神经保护作用中的功能，并支持 GSK3 作为这些促进存活的因子在颗粒神经元中的重要汇聚点的作用。
