論文 - 詳細
| RRC ID | 59361 |
|---|---|
| 著者 | Jiang Q, Li K, Lu WJ, Li S, Chen X, Liu XJ, Yuan J, Ding Q, Lan F, Cai SQ. |
| タイトル | Identification of small-molecule ion channel modulators in C. elegans channelopathy models. |
| ジャーナル | Nat Commun |
| 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. |
| 巻・号 | 9(1) |
| ページ | 3941 |
| 公開日 | 2018-9-26 |
| DOI | 10.1038/s41467-018-06514-5 |
| PII | 10.1038/s41467-018-06514-5 |
| PMID | 30258187 |
| PMC | PMC6158242 |
| MeSH | Animals Animals, Genetically Modified Caenorhabditis elegans Channelopathies / drug therapy Channelopathies / genetics* Channelopathies / metabolism Disease Models, Animal Diterpenes / pharmacology Diterpenes / therapeutic use Drug Evaluation, Preclinical Ether-A-Go-Go Potassium Channels / antagonists & inhibitors Ether-A-Go-Go Potassium Channels / genetics* Ether-A-Go-Go Potassium Channels / metabolism Humans Myocytes, Cardiac / drug effects Myocytes, Cardiac / metabolism Phorbol Esters / pharmacology Phorbol Esters / therapeutic use Protein Kinase C / metabolism Triterpenes / pharmacology Triterpenes / therapeutic use |
| IF | 11.878 |
| 引用数 | 2 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 2 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 線虫 | tm3232 |