Propofol inhibits hERG K+ channels and enhances the inhibition effects on its mutations in HEK293 cells
文献类型：期刊论文
| 作者 | Han, Sheng-Na1; Jing, Ying2; Yang, Lin-Lin1,4; Zhang, Zhao3; Zhang, Li-Rong1 |
| 刊名 | EUROPEAN JOURNAL OF PHARMACOLOGY
 |
| 出版日期 | 2016-11-15 |
| 卷号 | 791页码:168-178 |
| 关键词 | Propofol QT prolongation Human ether-a-go-go-related gene (hERG) Protein trafficking Gene mutation |
| ISSN号 | 0014-2999 |
| DOI | 10.1016/j.ejphar.2016.08.028 |
| 文献子类 | Article |
| 英文摘要 | 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 mu M. 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 mu M, 3.3 +/- 1.2 mu M, and 5.9 +/- 1.9 mu M, 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. (C) 2016 Elsevier B.V. All rights reserved. |
| WOS关键词 | LONG-QT SYNDROME ; TORSADES-DE-POINTES ; VENTRICULAR-TACHYCARDIA ; CARDIAC REPOLARIZATION ; ANESTHETIC PROPOFOL ; METABOLIC-ACIDOSIS ; GENE CHANNEL ; INFUSION ; INTERVAL ; SEVOFLURANE |
| 资助项目 | National Natural Science Foundation of China[81200138] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000388827700018 |
| 出版者 | ELSEVIER SCIENCE BV |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/275808]  |
| 专题 | 新药研究国家重点实验室 中科院受体结构与功能重点实验室 |
| 通讯作者 | Zhang, Zhao; Zhang, Li-Rong |
| 作者单位 | 1.Zhengzhou Univ, Dept Pharmacol, Basic Med Coll, Zhengzhou 450001, Peoples R China; 2.Zhengzhou Univ, Dept Physiol & Neurobiol, Basic Med Coll, Zhengzhou 450001, Peoples R China; 3.Nanjing Normal Univ, Coll Life Sci, Jiangsu Key Lab Mol & Med Biotechnol, Nanjing 210046, Jiangsu, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Han, Sheng-Na,Jing, Ying,Yang, Lin-Lin,et al. Propofol inhibits hERG K+ channels and enhances the inhibition effects on its mutations in HEK293 cells[J]. EUROPEAN JOURNAL OF PHARMACOLOGY,2016,791:168-178. |
| APA | Han, Sheng-Na,Jing, Ying,Yang, Lin-Lin,Zhang, Zhao,&Zhang, Li-Rong.(2016).Propofol inhibits hERG K+ channels and enhances the inhibition effects on its mutations in HEK293 cells.EUROPEAN JOURNAL OF PHARMACOLOGY,791,168-178. |
| MLA | Han, Sheng-Na,et al."Propofol inhibits hERG K+ channels and enhances the inhibition effects on its mutations in HEK293 cells".EUROPEAN JOURNAL OF PHARMACOLOGY 791(2016):168-178. |
入库方式： OAI收割
来源：上海药物研究所
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