Modulation of hERG potassium channel gating normalizes action potential duration prolonged by dysfunctional KCNQ1 potassium channel
文献类型：期刊论文
| 作者 | Zhang, Hongkang5; Zou, Beiyan5; Yu, Haibo5; Moretti, Alessandra3,4; Wang, Xiaoying1; Yan, Wei5; Babcock, Joseph J.5; Bellin, Milena3,4; McManus, Owen B.5,6; Tomaselli, Gordon2 |
| 刊名 | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
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| 出版日期 | 2012-07-17 |
| 卷号 | 109期号:29页码:11866-11871 |
| 关键词 | stem cells drugs |
| ISSN号 | 0027-8424 |
| DOI | 10.1073/pnas.1205266109 |
| 文献子类 | Article |
| 英文摘要 | Long QT syndrome (LQTS) is a genetic disease characterized by a prolonged QT interval in an electrocardiogram (ECG), leading to higher risk of sudden cardiac death. Among the 12 identified genes causal to heritable LQTS, similar to 90% of affected individuals harbor mutations in either KCNQ1 or human ether-a-go-go related genes (hERG), which encode two repolarizing potassium currents known as I-Ks and I-Kr. The ability to quantitatively assess contributions of different current components is therefore important for investigating disease phenotypes and testing effectiveness of pharmacological modulation. Here we report a quantitative analysis by simulating cardiac action potentials of cultured human cardiomyocytes to match the experimental waveforms of both healthy control and LQT syndrome type 1 (LQT1) action potentials. The quantitative evaluation suggests that elevation of I-Kr by reducing voltage sensitivity of inactivation, not via slowing of deactivation, could more effectively restore normal QT duration if I-Ks is reduced. Using a unique specific chemical activator for I-Kr that has a primary effect of causing a right shift of V-1/2 for inactivation, we then examined the duration changes of autonomous action potentials from differentiated human cardiomyocytes. Indeed, this activator causes dose-dependent shortening of the action potential durations and is able to normalize action potentials of cells of patients with LQT1. In contrast, an I-Kr chemical activator of primary effects in slowing channel deactivation was not effective in modulating action potential durations. Our studies provide both the theoretical basis and experimental support for compensatory normalization of action potential duration by a pharmacological agent. |
| WOS关键词 | LONG-QT SYNDROME ; TORSADE-DE-POINTES ; K+ CHANNEL ; 1,3-BIS-(2-HYDROXY-5-TRIFLUOROMETHYL-PHENYL)-UREA NS1643 ; CARDIAC-ARRHYTHMIAS ; LQT3 MODELS ; IN-VITRO ; REPOLARIZATION ; MECHANISMS ; FORM |
| 资助项目 | National Institutes of Health[GM078579] ; National Institutes of Health[MH084691] ; Maryland Stem Cell Research Fund[2010-MSCRFE-0164-00] ; European Research Council[ERC 261053] ; German Research Foundation (Research Unit 923)[Mo 2217/1-1] ; German Research Foundation (Research Unit 923)[La 1238 3-1/4-1] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| WOS记录号 | WOS:000306837100075 |
| 出版者 | NATL ACAD SCIENCES |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/278013]  |
| 专题 | 神经药理学研究国际科学家工作站 国家新药筛选中心 |
| 通讯作者 | Li, Min |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Chinese Natl Drug Screening Ctr, Shanghai 201203, Peoples R China 2.Johns Hopkins Univ, Dept Cardiol, Sch Med, Baltimore, MD 21205 USA; 3.Tech Univ Munich, Div Cardiol, Dept Med 1, Klinikum Rechts Isar, D-81675 Munich, Germany; 4.Tech Univ Munich, German Heart Ctr Munich, Klinikum Rechts Isar, D-81675 Munich, Germany; 5.Johns Hopkins Univ, Dept Neurosci, High Throughput Biol Ctr, Baltimore, MD 21205 USA; 6.Johns Hopkins Univ, Johns Hopkins Ion Channel Ctr, Baltimore, MD 21205 USA; |
| 推荐引用方式 GB/T 7714 | Zhang, Hongkang,Zou, Beiyan,Yu, Haibo,et al. Modulation of hERG potassium channel gating normalizes action potential duration prolonged by dysfunctional KCNQ1 potassium channel[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2012,109(29):11866-11871. |
| APA | Zhang, Hongkang.,Zou, Beiyan.,Yu, Haibo.,Moretti, Alessandra.,Wang, Xiaoying.,...&Li, Min.(2012).Modulation of hERG potassium channel gating normalizes action potential duration prolonged by dysfunctional KCNQ1 potassium channel.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,109(29),11866-11871. |
| MLA | Zhang, Hongkang,et al."Modulation of hERG potassium channel gating normalizes action potential duration prolonged by dysfunctional KCNQ1 potassium channel".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 109.29(2012):11866-11871. |
入库方式： OAI收割
来源：上海药物研究所
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