凯胺的抗抑郁作用通过eIF4E启动细胞特异翻译
Argel Aguilar-Valles1,2,3, Danilo De Gregorio4,5, Edna Matta-Camacho4,6
1Department of Biochemistry and Goodman Cancer Centre, McGill University, Montreal, Quebec, Canada. argel.aguilavalles@carleton.ca.
Nature
|December 17, 2020
概括
胺及其代谢物 (2R,6R) - 胺的抗抑郁作用取决于真核细胞启动因子4E结合蛋白 (4E- BPs). 具体来说,激发性神经元中的4E-BP2和抑制性神经元中的4E-BP1和4E-BP2均调解这些抗抑郁作用.
科学领域:
- 神经科学
- 药理学
- 分子生物学
背景情况:
- 大型抑郁症 (MDD) 药物治疗面临挑战,超过30%的患者对SSRI等一线治疗有抗药性.
- 亚麻醉剂胺具有快速的抗抑郁作用,但其分子机制尚未完全理解.
- 建议胺的代谢物 (2R,6R) - 氨基胺 ((2R,6R) - HNK) 调解其抗抑郁作用.
研究的目的:
- 阐明胺和 (2R,6R) -HNK抗抑郁作用的分子机制.
- 调查4E-BPs在基他胺抗抑郁剂活性中介作用的真核启动因子.
- 确定4E-BPs发挥作用的特定神经元群体 (刺激性或抑制性).
主要方法:
- 研究了4E-BP1和4E-BP2在胺和 (2R,6R) - HNK抗抑郁药的作用.
- 在缺乏4E-BPs的小鼠中研究胺诱导的海马突触可塑性.
- 在特定神经元类型中的4E-BP遗传缺失的小鼠中检查了对胺和 (2R,6R) -HNK的行为反应.
主要成果:
- 4E-BP1和4E-BP2被确定为胺和 (2R,6R) - HNK抗抑郁药物的关键作用因子.
- 基胺诱导的海马突触可塑性依赖于4E-BP2,在较小程度上,依赖于4E-BP1.
- 激发性神经元中的4E-BP2以及抑制性神经元中的4E-BP1和4E-BP2均介于抗抑郁药的活性.
结论:
- 4E- 结合蛋白 (4E- BP) 是胺及其代谢物 (2R,6R) - HNK抗抑郁活性的核心.
- 抑制神经元中的4E-BP2遗传缺失模仿了抗抑郁药的作用,并阻断了胺对神经传递的影响.
- 这些发现强调4E-BP是理解和开发新型抗抑郁药物治疗的关键分子标.
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