Identification of small-molecule ion channel modulators in C. elegans channelopathy models.
Identification of small-molecule ion channel modulators in C. elegans channelopathy models.
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秀丽隐杆线虫通道病模型中小分子离子通道调节剂的鉴定。
DOI：
10.1038/s41467-018-06514-5
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发表时间：
2018-09-26
影响因子：
16.6
通讯作者：
Cai SQ
中科院分区：
文献类型：
--
作者：
Jiang Q;Li K;Lu WJ;Li S;Chen X;Liu XJ;Yuan J;Ding Q;Lan F;Cai SQ
离子通道是重要的治疗靶点，但由于缺乏允许在生理背景下进行高通量筛选的测定，离子通道药物的发现仍然具有挑战性。在这里，我们报告C。基于线虫表型筛选离子通道药物的方法。修饰的人ether-a-go-go相关基因（hERG）钾通道在C. elegans导致产卵和运动缺陷，这为筛选小分子通道调节剂提供了指标。在表达hERGA 561 V的蠕虫中进行筛选，该病毒携带已知与长QT综合征相关的运输缺陷突变A561 V，鉴定了两种功能性校正剂Prostratin和巨大戟二萜醇-3，20-二苯甲酸酯。这些化合物激活PKCε信号传导，从而在通道的孔区域磷酸化S606，以促进hERGA 561 V运输至质膜。重要的是，这些化合物纠正了携带杂合CRISPR/Cas9编辑的hERGA 561 V的hiPSC衍生的心肌细胞中的电生理异常。因此，我们已经开发了一种体内高通量方法，用于筛选在治疗通道病中具有治疗潜力的化合物。电压门控K+通道人类ether-a-go-go-related基因（hERG）的突变导致长QT综合征，引起危及生命的心律失常。在这里，作者使用C。elegans作为一个平台来运行一个通道病药物筛选，确定药物靶向hERG突变体。
Ion channels are important therapeutic targets, but the discovery of ion channel drugs remains challenging due to a lack of assays that allow high-throughput screening in the physiological context. Here we report C. elegans phenotype-based methods for screening ion channel drugs. Expression of modified human ether-a-go-go-related gene (hERG) potassium channels in C. elegans results in egg-laying and locomotive defects, which offer indicators for screening small-molecule channel modulators. Screening in worms expressing hERGA561V, which carries a trafficking-defective mutation A561V known to associate with long-QT syndrome, identifies two functional correctors Prostratin and ingenol-3,20-dibenzoate. These compounds activate PKCε signaling and consequently phosphorylate S606 at the pore region of the channel to promote hERGA561V trafficking to the plasma membrane. Importantly, the compounds correct electrophysiological abnormalities in hiPSC-derived cardiomyocytes bearing a heterozygous CRISPR/Cas9-edited hERGA561V. Thus, we have developed an in vivo high-throughput method for screening compounds that have therapeutic potential in treating channelopathies. Mutations in the voltage-gated K+ channel human ether-a-go-go-related gene (hERG) lead to Long-QT syndrome, causing life-threatening cardiac arrhythmia. Here the authors use C. elegans as a platform to run a channelopathy drug screen, identifying drugs to target hERG mutants.
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影响因子：
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作者：
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