Rapid antidepressants stimulate the decoupling of GABA(B) receptors from GIRK/Kir3 channels through increased protein stability of 14-3-3η.
Rapid antidepressants stimulate the decoupling of GABA(B) receptors from GIRK/Kir3 channels through increased protein stability of 14-3-3η.
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DOI：
10.1038/mp.2014.165
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发表时间：
2015-03
影响因子：
11
通讯作者：
Raab-Graham, K. F.
中科院分区：
文献类型：
--
作者：
Workman, E. R.;Haddick, P. C. G.;Bush, K.;Dilly, G. A.;Niere, F.;Zemelman, B. V.;Raab-Graham, K. F.
单次注射N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂可产生快速的抗抑郁反应。突触结构和组成的持久变化是这些药物有效性的基础。我们最近发现，快速抗抑郁药引起γ-氨基丁酸受体（GABABR）信号通路的转变，使得GABABR激活从开放内向整流钾通道（Kir/GIRK）转变为增加静息树突状钙信号和哺乳动物雷帕霉素靶点活性。然而，人们对引发这种转变的分子和生化机制知之甚少。在此，我们表明，GABABR信号Kir 3（GIRK）通道减少与NMDAR封锁。阻断NMDAR信号传导使衔接蛋白14-3-3η稳定，衔接蛋白14 -3-3η使来自Kir 3的GABABR信号传导稳定，并且是快速抗抑郁功效所需的。与这些结果一致，我们发现参与GABABR信号传导的关键蛋白在抑郁模型中和快速抗抑郁药中双向变化。在社交失败的啮齿类动物中，抑郁症模型，海马中GABABR和14-3-3η水平降低。NMDAR拮抗剂AP 5和Ro-25-6981作为快速抗抑郁药，增加GABABR和14-3-3η表达并降低Kir3.2。总之，这些数据表明GABABR功能的转变需要由14-3-3η介导的GABABR-Kir 3通道活性的丧失。我们的研究结果支持了14-3-3η在快速抗抑郁药疗效中的核心作用，并定义了GABABR信号传导中活性依赖性改变的关键分子机制。
A single injection of N-methyl-D-aspartate receptor (NMDAR) antagonists produces a rapid antidepressant response. Lasting changes in the synapse structure and composition underlie the effectiveness of these drugs. We recently discovered that rapid antidepressants cause a shift in the γ-aminobutyric acid receptor (GABABR) signaling pathway, such that GABABR activation shifts from opening inwardly rectifiying potassium channels (Kir/GIRK) to increasing resting dendritic calcium signal and mammalian Target of Rapamycin activity. However, little is known about the molecular and biochemical mechanisms that initiate this shift. Herein, we show that GABABR signaling to Kir3 (GIRK) channels decreases with NMDAR blockade. Blocking NMDAR signaling stabilizes the adaptor protein 14-3-3η, which decouples GABABR signaling from Kir3 and is required for the rapid antidepressant efficacy. Consistent with these results, we find that key proteins involved in GABABR signaling bidirectionally change in a depression model and with rapid antidepressants. In socially defeated rodents, a model for depression, GABABR and 14-3-3η levels decrease in the hippocampus. The NMDAR antagonists AP5 and Ro-25-6981, acting as rapid antidepressants, increase GABABR and 14-3-3η expression and decrease Kir3.2. Taken together, these data suggest that the shift in GABABR function requires a loss of GABABR-Kir3 channel activity mediated by 14-3-3η. Our findings support a central role for 14-3-3η in the efficacy of rapid antidepressants and define a critical molecular mechanism for activity-dependent alterations in GABABR signaling.
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影响因子：
15.9
作者：
Holtzheimer, Paul E.;Mayberg, Helen S.
通讯作者：
Mayberg, Helen S.
影响因子：
64.8
作者：
Autry, Anita E.;Adachi, Megunai;Nosyreva, Elena;Na, Elisa S.;Los, Maarten F.;Cheng, Peng-fei;Kavalali, Ege T.;Monteggia, Lisa M.
通讯作者：
Monteggia, Lisa M.
DOI：
10.1002/ajmg.b.30927
发表时间：
2009-10-05
影响因子：
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作者：
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通讯作者：
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影响因子：
5.3
作者：
Hayashi, T;Huganir, RL
通讯作者：
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影响因子：
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作者：
aan het Rot, Marije;Collins, Katherine A.;Mathew, Sanjay J.
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