NMDAR2B tyrosine phosphorylation regulates anxiety-like behavior and CRF expression in the amygdala.
NMDAR2B tyrosine phosphorylation regulates anxiety-like behavior and CRF expression in the amygdala.
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DOI：
10.1186/1756-6606-3-37
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发表时间：
2010-11-30
期刊：
影响因子：
3.6
通讯作者：
Nakazawa T
中科院分区：
文献类型：
--
作者：
Delawary M;Tezuka T;Kiyama Y;Yokoyama K;Inoue T;Hattori S;Hashimoto R;Umemori H;Manabe T;Yamamoto T;Nakazawa T
焦虑症是一种高度流行和致残的精神疾病。越来越多的证据表明谷氨酸系统参与了焦虑症的病理生理学和治疗，尽管谷氨酸系统调节焦虑样行为的分子机制仍不清楚。在这项研究中，我们提供的证据表明，酪氨酸磷酸化的NMDA受体，离子型谷氨酸受体，有助于焦虑样行为。NMDA受体的GluN 2B亚基是酪氨酸磷酸化的：Tyr-1472是主要的磷酸化位点。表达GluN 2B的Tyr-1472-Phe突变体的纯合敲入小鼠在高架十字迷宫试验中显示出增强的焦虑样行为，该突变体可阻止该位点的磷酸化。促肾上腺皮质激素释放因子（CRF）的表达，这是重要的焦虑样行为的调节，是增加在敲入小鼠的杏仁核。此外，注射CRF受体拮抗剂可以减弱基因敲入小鼠增强的焦虑样行为。我们还表明，升高的十字迷宫暴露同时诱导Tyr-1472的去磷酸化和CRF表达增加。这些数据表明GluN 2B上的Tyr-1472磷酸化通过杏仁核中CRF表达的负调节对焦虑样行为很重要。
Anxiety disorders are a highly prevalent and disabling class of psychiatric disorders. There is growing evidence implicating the glutamate system in the pathophysiology and treatment of anxiety disorders, though the molecular mechanism by which the glutamate system regulates anxiety-like behavior remains unclear. In this study, we provide evidence suggesting that tyrosine phosphorylation of the NMDA receptor, an ionotropic glutamate receptor, contributes to anxiety-like behavior. The GluN2B subunit of the NMDA receptor is tyrosine-phosphorylated: Tyr-1472 is the major phosphorylation site. Homozygous knock-in mice that express a Tyr-1472-Phe mutant of GluN2B, which prevents phosphorylation of this site, show enhanced anxiety-like behavior in the elevated plus-maze test. Expression of corticotropin-releasing factor (CRF), which is important for the regulation of anxiety-like behavior, is increased in the amygdala of the knock-in mice. Furthermore, injection of CRF receptor antagonist attenuated the enhanced anxiety-like behavior of the knock-in mice. We also show that elevated plus-maze exposure simultaneously induced de-phosphorylation of Tyr-1472 and increased CRF expression. These data suggest that Tyr-1472 phosphorylation on GluN2B is important for anxiety-like behavior by negative regulation of CRF expression in the amygdala.
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