异氟烷抑制胱硫醚-β-合酶的结构基础及其在小鼠麻醉诱导的社会功能障碍中的作用。
Structural basis for the inhibition of cystathionine-β-synthase by isoflurane and its role in anaesthesia-induced social dysfunction in mice.
作者信息
He Mengfan, Wan Hanxi, Cong Peilin, Li Xinyang, Cheng Chun, Huang Xinwei, Zhang Qian, Wu Huanghui, Tian Li, Xu Ke, Xiong Lize
机构信息
Shanghai Key Laboratory of Anaesthesiology and Brain Functional Modulation, Translational Research Institute of Brain and Brain-Like Intelligence, Clinical Research Centre for Anaesthesiology and Perioperative Medicine, Department of Anaesthesiology and Perioperative Medicine, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
Shanghai Key Laboratory of Anaesthesiology and Brain Functional Modulation, Translational Research Institute of Brain and Brain-Like Intelligence, Clinical Research Centre for Anaesthesiology and Perioperative Medicine, Department of Anaesthesiology and Perioperative Medicine, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
出版信息
Br J Anaesth. 2025 Mar;134(3):746-758. doi: 10.1016/j.bja.2024.09.023. Epub 2024 Nov 26.
BACKGROUND
Anaesthesia has been shown to impair social functioning, but the underlying mechanisms remain largely unknown. The volatile anaesthetic isoflurane potentially disrupts the methionine cycle and trans-sulphuration pathway, contributing to social deficits. Cystathionine-β-synthase (CBS), a key enzyme in this pathway, might be targeted by isoflurane. We investigated the CBS-isoflurane interaction and its role in neuronal function and social behaviour.
METHODS
Mice aged 3-15 months were anaesthetised with 2 vol% isoflurane for 2 h, and social behaviours were tested 24 h after exposure. Alterations in neuronal activity were assessed using electrophysiological analysis in vivo. Pharmacological activators (S-adenosylmethionine [SAM]) or inhibitors (amino-oxyacetic acid [AOAA]), and adeno-associated virus (AAV) were used to modulate CBS activity. The binding site of isoflurane on CBS was determined using X-ray crystallography. A novel transgenic model with a point mutation knock-in was constructed to eliminate the CBS-isoflurane interaction.
RESULTS
Isoflurane inhibited CBS activity (by 0.35-fold [0.07] vs 1.00-fold [0.05]; P<0.001), leading to neuronal hypoactivity in the anterior cingulate cortex (ACC) and social impairments in adult and elderly mice. SAM, AOAA, and AAV interventions demonstrated a causal link. Structural and functional analysis identified the lysine 273 (K273) in CBS to be involved in isoflurane inhibition. CBS K273A knock-in mice exhibited increased CBS activity compared with wild-type littermates after isoflurane exposure (2.2-fold [0.22] vs 1.0-fold [0.28]; P<0.001), with successful alleviation of ACC neuronal hypoactivity and social dysfunction.
CONCLUSIONS
These findings reveal a crucial role for CBS inhibition by isoflurane in anaesthesia-induced social impairment.
背景
麻醉已被证明会损害社交功能，但其潜在机制在很大程度上仍不清楚。挥发性麻醉剂异氟烷可能会破坏蛋氨酸循环和转硫途径，导致社交缺陷。胱硫醚-β-合酶（CBS）是该途径中的一种关键酶，可能是异氟烷的作用靶点。我们研究了CBS与异氟烷的相互作用及其在神经元功能和社交行为中的作用。
方法
对3至15月龄的小鼠用2%体积分数的异氟烷麻醉2小时，并在暴露后24小时测试其社交行为。在体内使用电生理分析评估神经元活动的变化。使用药理学激活剂（S-腺苷甲硫氨酸[SAM]）或抑制剂（氨基氧乙酸[AOAA]）以及腺相关病毒（AAV）来调节CBS活性。使用X射线晶体学确定异氟烷在CBS上的结合位点。构建了一种具有点突变敲入的新型转基因模型，以消除CBS与异氟烷的相互作用。
结果
异氟烷抑制了CBS活性（0.35倍[0.07]对1.00倍[0.05]；P<0.001），导致成年和老年小鼠前扣带回皮质（ACC）的神经元活动减退以及社交障碍。SAM、AOAA和AAV干预证明了因果关系。结构和功能分析确定CBS中的赖氨酸273（K273）参与异氟烷抑制。与野生型同窝小鼠相比，异氟烷暴露后CBS K273A敲入小鼠的CBS活性增加（2.2倍[0.22]对1.0倍[0.28]；P<0.001），成功缓解了ACC神经元活动减退和社交功能障碍。
结论
这些发现揭示了异氟烷抑制CBS在麻醉诱导的社交损害中起关键作用。
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