Lithium activates the serine/threonine kinase Akt-1 and suppresses glutamate-induced inhibition of Akt-1 activity in neurons
Lithium activates the serine/threonine kinase Akt-1 and suppresses glutamate-induced inhibition of Akt-1 activity in neurons
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DOI：
10.1073/pnas.96.15.8745
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发表时间：
1999-07-20
影响因子：
11.1
通讯作者：
Chuang, DM
中科院分区：
文献类型：
--
作者：
Chalecka-Franaszek, E;Chuang, DM
本报告描述了锂和谷氨酸对丝氨酸/苏氨酸激酶Akt-1活性的调节作用。锂最常用于治疗双相情感障碍，但其治疗作用的机制尚不清楚。我们最近在培养的脑神经元和脑缺血动物模型中证明了锂对谷氨酸诱导的兴奋性毒性的保护作用，本研究旨在探讨磷酸肌醇3-激酶（PI 3-K）信号通路激活的Akt-1在介导谷氨酸兴奋毒性和锂保护小脑颗粒细胞中的作用。在血清存在下培养的小脑神经元中检测到高水平的Akt-1磷酸化和活性。用选择性PI 3-K抑制剂wortmannin和LY 294002处理prolampine，可消除Akt-1活性并诱导神经元死亡，这可通过长期锂预处理来减轻。细胞暴露于谷氨酸诱导Akt-1磷酸化和激酶活性的快速和可逆的丧失，这些作用与兴奋性毒性和caspase 3激活密切相关，并可被磷酸酶抑制剂阻止。冈田酸和caliculin A，长期锂预处理抑制谷氨酸诱导的Akt-1活性丧失，并加速其恢复至对照水平。单独锂处理诱导PI 3-K活性迅速增加，Akt-1磷酸化伴随激酶激活，这被PI 3-K抑制剂阻断。锂还增加了Akt下游生理靶点糖原合成酶激酶-3（GSK-3）的磷酸化，因此，Akt-1活性的调节似乎在谷氨酸兴奋毒性和锂神经保护机制中起关键作用。
This report describes a modulatory action of lithium and glutamate on the activity of serine/threonine kinase Akt-1, Lithium is most commonly used to treat bipolar disorder, but the mechanism of its therapeutic action remains unknown, We have recently demonstrated that lithium protects against glutamate-induced excitotoxicity in cultured brain neurons and in an animal model of cerebral ischemia, This study was undertaken to investigate the role of Akt-1, activated by the phosphatidylinositol 3-kinase (PI 3-K) signaling pathway, in mediating glutamate excitotoxicity and lithium protection in cerebellar granule cells. High levels of phosphorylation and activity of Akt-1 were detected in cerebellar neurons;cultured in the presence of serum. Protracted treatment with selective PI 3-K inhibitors, wortmannin and LY294002, abolished Akt-1 activity and induced neuronal death that could be reduced by long-term lithium pretreatment, Exposure of cells to glutamate induced a rapid and reversible loss of Akt-1 phosphorylation and kinase activity, These effects were closely correlated with excitotoxicity and caspase 3 activation and were prevented by phosphatase inhibitors, okadaic acid and caliculin A, Long-term lithium pretreatment suppressed glutamate-induced loss of Akt-1 activity and accelerated its recovery toward the control levels. Lithium treatment alone induced rapid increase in PI 3-K activity, and Akt-1 phosphorylation with accompanying kinase activation, which was blocked by PI 3-K inhibitors. Lithium also increased the phosphorylation of glycogen synthase kinase-3 (GSK-3), a downstream physiological target of Akt, Thus, modulation of Akt-1 activity appears to play a key role in the mechanism of glutamate excitotoxicity and lithium neuroprotection.