人类KCNT1通道调节剂的电生理特性以及氢奎宁和替佩定在KCNT1突变相关癫痫小鼠模型中的治疗潜力

IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Acta Pharmacologica Sinica Pub Date : 2025-05-01 Epub Date: 2025-01-27 DOI:10.1038/s41401-024-01457-8
Qing Guo, Jun Gan, En-Ze Wang, Yu-Ming Wei, Jie Xu, Yun Xu, Fei-Fei Zhang, Meng Cui, Meng-Xing Jia, Ming-Jian Kong, Qiong-Yao Tang, Zhe Zhang
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引用次数: 0

摘要

由hKCNT1钾通道的功能获得突变引起的癫痫患者是药物难治性的。在这项研究中,我们利用大脑cDNA文库克隆了一个新的人类KCNT1B通道异构体,并进行了膜片钳和分子对接分析,以表征13种药物的hKCNT1B通道的药理特性。在金鸡纳生物碱中,我们发现对苯二酚对hKCNT1B通道的阻断作用最强,尤其是对F313L突变体。此外,我们证实了止咳药替佩定也是hKCNT1B通道的有效抑制剂。随后,我们证明了这两种药物对KCNT1 Y777H突变雄性小鼠癫痫模型具有良好的治疗效果;因此,这两种药物都可以成为现成的抗癫痫药物。另一方面,我们证明了氯氮平和氯氮平通过与孔结构域残基相互作用来激活KCNT1通道,从而逆转KCNT1通道的衰竭。综上所述,我们的研究结果为调节KCNT1通道活性的机制提供了新的见解,并为治疗KCNT1突变相关癫痫的临床试验提供了重要的候选药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Electrophysiological characterization of human KCNT1 channel modulators and the therapeutic potential of hydroquinine and tipepidine in KCNT1 mutation-associated epilepsy mouse model.

Patients suffering epilepsy caused by the gain-of-function mutants of the hKCNT1 potassium channels are drug refractory. In this study, we cloned a novel human KCNT1B channel isoform using the brain cDNA library and conducted patch-clamp and molecular docking analyses to characterize the pharmacological properties of the hKCNT1B channel using thirteen drugs. Among cinchona alkaloids, we found that hydroquinine exerted the strongest blocking effect on the hKCNT1B channel, especially the F313L mutant. In addition, we confirmed the antitussive drug tipepidine was also a potent inhibitor of the hKCNT1B channel. Subsequently, we proved that these two drugs produced an excellent therapeutic effect on the epileptic model of KCNT1 Y777H mutant male mice; thus, both could be ready-to-use anti-epileptic drugs. On the other hand, we demonstrated that the activation of the KCNT1 channel by loxapine and clozapine was through interacting with pore domain residues to reverse the run-down of the KCNT1 channel. Taken together, our results provide new insights into the mechanism of the modulators in regulating the KCNT1 channel activity as well as important candidates for clinical tests in the treatment of KCNT1 mutant-associated epilepsy.

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来源期刊
Acta Pharmacologica Sinica
Acta Pharmacologica Sinica 医学-化学综合
CiteScore
15.10
自引率
2.40%
发文量
4365
审稿时长
2 months
期刊介绍: APS (Acta Pharmacologica Sinica) welcomes submissions from diverse areas of pharmacology and the life sciences. While we encourage contributions across a broad spectrum, topics of particular interest include, but are not limited to: anticancer pharmacology, cardiovascular and pulmonary pharmacology, clinical pharmacology, drug discovery, gastrointestinal and hepatic pharmacology, genitourinary, renal, and endocrine pharmacology, immunopharmacology and inflammation, molecular and cellular pharmacology, neuropharmacology, pharmaceutics, and pharmacokinetics. Join us in sharing your research and insights in pharmacology and the life sciences.
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