| 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
|
| リソース情報 |
| 線虫 |
tm3232 |
