In vivo regulation of GSK3 phosphorylation by cholinergic and NMDA receptors
In vivo regulation of GSK3 phosphorylation by cholinergic and NMDA receptors
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DOI：
10.1016/j.neurobiolaging.2005.03.003
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发表时间：
2006-03-01
影响因子：
4.2
通讯作者：
Jope, RS
中科院分区：
文献类型：
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作者：
De Sarno, P;Bijur, GN;Jope, RS
糖原合成酶-3(GSK3)被丝氨酸磷酸化抑制，参与阿尔茨海默病(AD)的神经病理过程。我们测试了两种治疗AD的策略，即抑制乙酰胆碱酯酶和N-甲基-D-天冬氨酸(NMDA)受体，是否调节了小鼠大脑中两种GSK3亚型的磷酸化状态。在小鼠的海马区、大脑皮层，磷酸化的Ser21-GSK3α和磷酸化的Ser9-GSK3β的表达水平出现了大幅、快速的升高。和纹状体后，用M受体激动剂匹罗卡品或乙酰胆碱酯酶抑制剂毒扁豆碱处理小鼠。用美金刚治疗。NMDA受体拮抗剂也增加了小鼠脑中两种GSK3亚型的丝氨酸-磷酸化。毒扁豆碱和美金刚联合应用可增加丝氨酸磷酸化的GSK3水平，与单独使用这两种药物的效果相当。这表明这两种药物的作用在重叠的GSK3池中收敛。因此。每类治疗阿尔茨海默病的药物都具有共同的特性，即在常见的酶库中增加GSK3的调节丝氨酸-磷酸化。(C)2005 Elsevier Inc.保留所有权利。
Glycogen synthase kinase-3 (GSK3), which is inhibited by serine-phosphorylation, is involved in the neuropathology of Alzheimer's disease (AD). We tested if the two therapeutic strategies used for AD, inhibition of acetylcholinesterase and of N-methyl-D-aspartate (NMDA) receptors, modulate the phosphorylation state of the two isoforms of GSK3 in mouse brain. Large, rapid increases in the levels of phospho-Ser2l-GSK3 alpha and phospho-Ser9-GSK3 beta occurred in mouse hippocampus, cerebral cortex. and striatum after treatment of mice with the muscarinic agonist pilocarpine or the acetylcholinesterase inhibitor physostigmine. Treatment with memantine. an NMDA receptor antagonist, also increased the serine-phosphorylation of both GSK3 isoforms in mouse brain. Co-adruinistration of physostigmine and memantine increased serine-phosphorylated GSK3 levels equally to that achieved by either agent alone. indicating that the actions of these two drugs converge on overlapping pools of GSK3. Thus. drugs in each class of therapeutic agents used for AD have the common property of increasing the regulatory serine-phosphorylation of GSK3 within common pools of the enzyme. (c) 2005 Elsevier Inc. All rights reserved.