Identification of small-molecule ion channel modulators in C. elegans channelopathy models

Qiang Jiang, Kai Li, Wen-Jing Lu, Shuang Li, Xin Chen, Xi-Juan Liu, Jie Yuan, Qiurong Ding, Feng Lan () and Shi-Qing Cai ()
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Qiang Jiang: Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Kai Li: Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Wen-Jing Lu: Capital Medical University
Shuang Li: University of Chinese Academy of Sciences
Xin Chen: Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Xi-Juan Liu: Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Jie Yuan: Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Qiurong Ding: Chinese Academy of Sciences
Feng Lan: Capital Medical University
Shi-Qing Cai: Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-06514-5

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