In vivo regulation of glycogen synthase kinase-3β (GSK3β) by serotonergic activity in mouse brain
In vivo regulation of glycogen synthase kinase-3β (GSK3β) by serotonergic activity in mouse brain
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DOI：
10.1038/sj.npp.1300439
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发表时间：
2004-08-01
影响因子：
7.6
通讯作者：
Jope, RS
中科院分区：
文献类型：
--
作者：
Li, XH;Zhu, W;Jope, RS
本研究的目的是确定在抑郁症中受损的多巴胺能活性是否调节小鼠脑中糖原合成酶激酶-3 β（GSK 3 β）的磷酸化。GSK 3 β受丝氨酸-9上的磷酸化抑制，并且是情绪稳定剂锂的靶点。在给小鼠施用d-芬氟拉明以刺激5-羟色胺（5-HT）释放并减少其再摄取，以及氯吉林以抑制5-HT催化剂后，在前额叶皮质、海马和纹状体中磷酸化-Ser 9-GSK 3 β的水平是对照水平的300-400%。单胺再吸收抑制剂百忧解和丙咪嗪治疗也增加了磷酸-Ser 9-GSK 3 β的水平。使用受体选择性激动剂和拮抗剂，发现5 HT 1A受体介导磷酸-Ser 9-GSK 3 β水平的增加，而5 HT 2受体介导磷酸-Ser 9-GSK 3 β水平的减少。这表明，通过这些5 HT受体亚型的相反作用之间的平衡来实现GSK 3 β磷酸化的多巴胺能调节。这些发现首次证明，多巴胺能活性调节GSK 3 β的磷酸化，并表明这种调节发生在体内哺乳动物脑中。这些结果提高了GSK 3 β抑制性控制受损可能发生在多巴胺能活性失调的情况下的可能性，如情绪障碍。
The goal of this study was to determine if serotonergic activity, which is impaired in depression, regulates the phosphorylation of glycogen synthase kinase-3beta (GSK3beta) in mouse brain in vivo, GSK3beta is inhibited by phosphorylation on serine-9 and is a target of the mood stabilizer lithium. Following administration to mice of d-fenfluramine to stimulate serotonin (5HT) release and reduce its reuptake, and clorgyline to inhibit 5HT catabolism, levels of phospho-Ser9-GSK3beta were 300-400% of control levels in the prefrontal cortex, hippocampus, and striatum. Treatment with monoamine reuptake inhibitors fluoxetine and imipramine also increased the level of phospho-Ser9-GSK3beta. Using receptor selective agonists and antagonists, 5HT I A receptors were found to mediate increases, and 5HT2 receptors decreases, in phospho-Ser9-GSK3beta levels. This indicates that serotonergic regulation of the phosphorylation of GSK3beta is achieved by a balance between the opposing actions of these 5HT receptor subtypes, These findings demonstrate for the first time that serotonergic activity regulates the phosphorylation of GSK3beta and show that this regulation occurs in mammalian brain in vivo. These results raise the possibility that impaired inhibitory control of GSK3beta may occur in conditions where serotonergic activity is dysregulated, such as in mood disorders.