title: Propofol inhibits hERG K+channels and enhances the inhibition effects on its mutations in HEK293 cells.
abstract: 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±6.4μM. 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 IC50of propofol was calculated as 14.2±2.8μM, 3.3±1.2μM, and 5.9±1.9μM, 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.
authors: Department of Pharmacology, Basic Medical College, Zhengzhou University, Zhengzhou 450001, China.
authors: Sheng-Na
authors: SN
authors: Han
authors: Department of Physiology and Neurobiology, Basic Medical College, Zhengzhou University, Zhengzhou 450001, China.
authors: Ying
authors: Y
authors: Jing
authors: Department of Pharmacology, Basic Medical College, Zhengzhou University, Zhengzhou 450001, China; Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors: Lin-Lin
authors: LL
authors: Yang
authors: Jiangsu Key Laboratory for Molecular & Medical Biotechnology, College of Life Science in Nanjing Normal University, Nanjing 210046, China. Electronic address: zhangzhao@njnu.edu.cn.
authors: Zhao
authors: Z
authors: Zhang
authors: Department of Pharmacology, Basic Medical College, Zhengzhou University, Zhengzhou 450001, China. Electronic address: zhanglirongzzu@126.com.
authors: Li-Rong
authors: LR
authors: Zhang
mesh_terms: D004305:Dose-Response Relationship, Drug; D055724:Electrophysiological Phenomena / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D009154:Mutation; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015742:Propofol / Q000494:pharmacology*
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers; D015742:Propofol
keywords: DMSO (PubChem CID: 679); EDTA (PubChem CID: 6049); Gene mutation; HEPES (PubChem CID: 23831); Human ether-a-go-go-related gene (hERG); Propofol; Protein trafficking; QT prolongation; Triton X-100 (PubChem CID: 5590); deoxycholate (PubChem CID: 222528); midazolam (PubChem CID: 4192); penicillin (PubChem CID: 5904); propofol (PubChem CID: 4943); streptomycin (PubChem CID: 19649)