State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, 430030, China.
Adv Sci (Weinh). 2024 Sep;11(34):e2400205. doi: 10.1002/advs.202400205. Epub 2024 Jul 4.
Physical exercise has beneficial effect on anxiety disorders, but the underlying molecular mechanism remains largely unknown. Here, it is demonstrated that physical exercise can downregulate the S-nitrosylation of gephyrin (SNO-gephyrin) in the basolateral amygdala (BLA) to exert anxiolytic effects. It is found that the level of SNO-gephyrin is significantly increased in the BLA of high-anxiety rats and a downregulation of SNO-gephyrin at cysteines 212 and 284 produced anxiolytic effect. Mechanistically, inhibition of SNO-gephyrin by either Cys212 or Cys284 mutations increased the surface expression of GABAR γ2 and the subsequent GABAergic neurotransmission, exerting anxiolytic effect in male rats. On the other side, overexpression of neuronal nitric oxide synthase in the BLA abolished the anxiolytic-like effects of physical exercise. This study reveals a key role of downregulating SNO-gephyrin in the anxiolytic effects of physical exercise, providing a new explanation for protein post-translational modifications in the brain after exercise.
体育锻炼对焦虑症有有益的影响，但潜在的分子机制在很大程度上尚不清楚。在这里，研究表明，体育锻炼可以下调基底外侧杏仁核（BLA）中神经胶质原纤维酸性蛋白（gephyrin）的 S-亚硝基化（SNO-gephyrin），从而发挥抗焦虑作用。研究发现，高焦虑大鼠的 BLA 中 SNO-gephyrin 的水平显著增加，而 Cys212 和 Cys284 上 SNO-gephyrin 的下调会产生抗焦虑作用。从机制上讲，通过 Cys212 或 Cys284 突变抑制 SNO-gephyrin 会增加 GABARγ2 的表面表达和随后的 GABA 能神经传递，从而在雄性大鼠中发挥抗焦虑作用。另一方面，BLA 中神经元型一氧化氮合酶的过表达会消除体育锻炼的抗焦虑样作用。这项研究揭示了下调 SNO-gephyrin 在体育锻炼抗焦虑作用中的关键作用，为运动后大脑中蛋白质的翻译后修饰提供了新的解释。
