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锂通过抑制磷酸肌醇 3-激酶介导的 Akt 磷酸化来增强 GSK-3β 的活性。

Lithium potentiates GSK-3β activity by inhibiting phosphoinositide 3-kinase-mediated Akt phosphorylation.

机构信息

Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan.

Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan.

出版信息

Biochem Biophys Res Commun. 2014 Jul 18;450(1):746-9. doi: 10.1016/j.bbrc.2014.06.041. Epub 2014 Jun 17.

DOI:10.1016/j.bbrc.2014.06.041
PMID:24950409
Abstract

Accumulating evidence has pointed to the direct inhibitory action of lithium, an anti-depressant, on GSK-3β. The present study investigated further insight into lithium signaling pathways. In the cell-free assay Li2CO3 significantly inhibited phosphoinositide 3-kinase (PI3K)-mediated phosphorylation of Akt1 at Ser473, but Li2CO3 did not affect PI3K-mediated PI(3,4,5)P3 production and 3-phosphoinositide-dependent protein kinase 1 (PDK1)-mediated phosphorylation of Akt1 at Thr308. This indicates that lithium could enhance GSK-3β activity by suppressing Akt-mediated Ser9 phosphorylation of GSK-3β in association with inhibition of PI3K-mediated Akt activation. There was no direct effect of Li2CO3 on Akt1-induced phosphorylation of GSK-3β at Ser9, but otherwise Li2CO3 significantly reduced GSK-3β-mediated phosphorylation of β-catenin at Ser33/37 and Thr41. This indicates that lithium directly inhibits GSK-3β in an Akt-independent manner. In rat hippocampal slices Li2CO3 significantly inhibited phosphorylation of Akt1/2 at Ser473/474, GSK-3β at Ser9, and β-catenin at Ser33/37 and Thr41. Taken together, these results indicate that lithium exerts its potentiating and inhibiting bidirectional actions on GSK-3β activity.

摘要

越来越多的证据表明，抗抑郁药锂可以直接抑制 GSK-3β。本研究进一步探讨了锂信号通路。在无细胞测定中，Li2CO3 显著抑制 Akt1 丝氨酸 473 位的磷酸化，而 Li2CO3 不影响 PI3K 介导的 PI(3,4,5)P3 生成和 3-磷酸肌醇依赖性蛋白激酶 1(PDK1)介导的 Akt1 苏氨酸 308 位的磷酸化。这表明锂可以通过抑制 Akt 激活来增强 GSK-3β 活性，从而抑制 Akt 介导的 GSK-3β 丝氨酸 9 磷酸化。Li2CO3 对 Akt1 诱导的 GSK-3β 丝氨酸 9 位磷酸化没有直接影响，但 Li2CO3 显著降低了 GSK-3β 介导的β-连环蛋白丝氨酸 33/37 和苏氨酸 41 位的磷酸化。这表明锂以 Akt 非依赖性方式直接抑制 GSK-3β。在大鼠海马切片中，Li2CO3 显著抑制 Akt1/2 丝氨酸 473/474、GSK-3β 丝氨酸 9 和 β-连环蛋白丝氨酸 33/37 和苏氨酸 41 位的磷酸化。总之，这些结果表明锂对 GSK-3β 活性具有双向增强和抑制作用。

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