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Microsc Res Tech ; 81(6): 663-668, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29573040

RESUMO

Mutations in genes related to long QT syndrome (LQTS) is recognized as an independent risk of drug-induced LQTS. We previously screened a mutation F463L in a Chinese patient with LQT2, syncope, and epilepsy. Here, we planned to illustrate how F463L influences the action of dofetilide on hERG channels. F463L-hERG plasmids were transfected into the stable Human Embryonic Kidney 293 (HEK293) cells expressing WT-hERG to generate heterozygous mutant (WT + F463L-hERG). Whole-cell patch clamp and laser confocal scanning microscopy were used to evaluate electrophysiological consequences and the membrane distribution of hERG protein. In comparison of WT-hERG channels exposed to dofetilide, heterozygous F463L-hERG channels showed a reduction in the density of tail currents when exposed amidarone. F463L-hERG also altered the action of dofetilide on the gating properties of hERG channels. Images of dofetilide-treated cells expressing heterozygous F463L showed a severe retention and reduction of protein expression on the membrane compared to WT. In conclusion, dofetilide displays a powerful inhibitory effect on the currents from cells expressing heterozygous F463L, thus showing an additive suppression of currents by F463L with dofetilide.


Assuntos
Canais de Potássio Éter-A-Go-Go/genética , Canais de Potássio Éter-A-Go-Go/metabolismo , Síndrome do QT Longo/genética , Fenetilaminas/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Sulfonamidas/farmacologia , Linhagem Celular , Células HEK293 , Humanos , Microscopia Confocal , Mutação/genética , Técnicas de Patch-Clamp , Plasmídeos/genética
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