کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2530786 1558889 2016 11 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Propofol inhibits hERG K+ channels and enhances the inhibition effects on its mutations in HEK293 cells
موضوعات مرتبط
علوم زیستی و بیوفناوری علم عصب شناسی علوم اعصاب سلولی و مولکولی
پیش نمایش صفحه اول مقاله
Propofol inhibits hERG K+ channels and enhances the inhibition effects on its mutations in HEK293 cells
چکیده انگلیسی

QT interval prolongation, a potential risk for arrhythmias, may result from gene polymorphisms relevant to cardiomyocyte repolarization. Another noted cause of QT interval prolongation is the administration of chemical compounds such as anesthetics, which may affect a specific type of cardiac K+ channel encoded by the human ether-a-go-go-related gene (hERG).hERG K+ current was recorded using whole-cell patch clamp in human embryonic kidney (HEK293) cells expressing wild type (WT) or mutated hERG channels. Expression of hERG K+ channel proteins was evaluated using western blot and confirmed by fluorescent staining and imaging. Computational modeling was adopted to identify the possible binding site(s) of propofol with hERG K+ channels. Propofol had a significant inhibitory effect on WT hERG K+ currents in a concentration-dependent manner, with a half-maximal inhibitory concentration (IC50) of 60.9±6.4 μM. Mutations in drug-binding sites (Y652A or F656C) of the hERG channel were found to attenuate hERG current blockage by propofol. However, propofol did not inhibit the trafficking of hERG protein to the cell membrane. Meanwhile, for the three selective hERG K+ channel mutant heterozygotes WT/Q738X-hERG, WT/A422T-hERG, and WT/H562P-hERG, the IC50 of propofol was calculated as 14.2±2.8 μM, 3.3±1.2 μM, and 5.9±1.9 μM, respectively, which were much lower than that for the wild type.These findings indicate that propofol may potentially increase QT interval prolongation risk in patients via direct inhibition of the hERG K+ channel, especially in those with other concurrent triggering factors such as hERG gene mutations.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: European Journal of Pharmacology - Volume 791, 15 November 2016, Pages 168–178
نویسندگان
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