小鼠神经肌肉连接处24-羟基胆固醇介导的神经递质释放调节的频率依赖机制:活性氧的作用。

IF 3.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Irina V. Kovyazina, Kamilla A. Mukhutdinova, Alexey M. Petrov
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引用次数: 0

摘要

神经元特异性酶CYP46A1将胆固醇转化为24-羟基胆固醇(24-HC),其穿过脑血屏障,进入体循环。24-HC的产生取决于突触和代谢活动,并在衰老和神经退行性疾病期间发生显著变化。先前的研究表明,在20 Hz的神经刺激下,24-HC(0.4µM)的长时间应用可以通过提高小鼠神经肌肉连接处(NMJs)的NO合成来抑制突触囊泡向胞外分泌的募集。本研究采用微电极记录突触后反应,荧光跟踪细胞内分泌、NO和活性氧(ROS)的产生,研究了24-HC在10 Hz和70 Hz神经放电时对神经肌肉传递的影响。在10hz刺激下,24-HC减少神经递质释放和突触囊泡参与胞吐。这与NO合成升高有关,而ROS生成没有明显变化。然而,在70 Hz活动下,24-HC增加了胞吐过程中突触囊泡的募集,同时抑制NO合成和增强ROS产生。nadph氧化酶抑制剂VAS2870抑制了24- hc介导的ROS生成的增加,抗氧化剂n -乙酰半胱氨酸完全阻止了70 Hz活动期间24- hc依赖性神经传递的增强和NO合成的抑制。同样,蛋白激酶C抑制剂chelerythrine在70 Hz刺激下阻断了24- hc介导的胞吐增强和NO生成的衰减。因此,24-HC在中频活动下抑制神经传递,可能是通过提高NO合成,但在高频神经放电过程中,它通过NADPH氧化酶/ROS/蛋白激酶C途径增强神经递质释放和突触囊泡募集到胞外。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Frequency-Dependent Mechanism of 24-Hydroxycholesterol-Mediated Modulation of Neurotransmitter Release at the Mouse Neuromuscular Junction: The Role of Reactive Oxygen Species

Neuron-specific enzyme CYP46A1 converts cholesterol to 24-hydroxycholesterol (24-HC), which crosses the brain blood barrier, entering the systemic circulation. Production of 24-HC depends on synaptic and metabolic activity and changes significantly during aging and neurodegenerative diseases. Previously, it was shown that prolonged application of 24-HC (0.4 µM) suppressed recruitment of synaptic vesicles to exocytosis during 20 Hz nerve stimulation acting via elevation of NO synthesis at the mouse neuromuscular junctions (NMJs). Here, using microelectrode recording of postsynaptic responses and fluorescent trackers for endo-exocytosis, NO and reactive oxygen species (ROS) production, the effect of 24-HC on neuromuscular transmission at 10 Hz and 70 Hz nerve firing was studied. At 10 Hz stimulation, 24-HC decreased neurotransmitter release and synaptic vesicle involvement in exocytosis. This was associated with elevation of NO synthesis without marked changes in ROS generation. However, at 70 Hz activity, 24-HC increased the recruitment of synaptic vesicles in exocytosis in combination with attenuation of NO synthesis and enhancement of ROS production. 24-HC-mediated increase in ROS production was suppressed by NADPH-oxidase inhibitor VAS2870, and antioxidant N-acetylcysteine completely prevented 24-HC-dependent potentiation of neurotransmission and suppression of NO synthesis during 70 Hz activity. Similarly, protein kinase C inhibitor chelerythrine blocked 24-HC-mediated enhancement of exocytosis and attenuation of NO generation at 70 Hz stimulation. Thus, 24-HC suppresses neurotransmission at moderate-frequency activity, probably via elevation of NO synthesis, but it potentiates neurotransmitter release and synaptic vesicle recruitment into exocytosis during high-frequency nerve firing via an NADPH oxidase/ROS/protein kinase C pathway.

Graphical Abstract

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来源期刊
Neurochemical Research
Neurochemical Research 医学-神经科学
CiteScore
7.70
自引率
2.30%
发文量
320
审稿时长
6 months
期刊介绍: Neurochemical Research is devoted to the rapid publication of studies that use neurochemical methodology in research on nervous system structure and function. The journal publishes original reports of experimental and clinical research results, perceptive reviews of significant problem areas in the neurosciences, brief comments of a methodological or interpretive nature, and research summaries conducted by leading scientists whose works are not readily available in English.
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