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Comparison of Gating Properties and Use-Dependent Block of Na(v)1.5 and Na(v)1.7 Channels by Anti-Arrhythmics Mexiletine and Lidocaine
Wang, Ying1; Mi, Jianxun2; Lu, Ka3; Lu, Yanxin1,3; Wang, KeWei1,3,4
刊名PLOS ONE
2015-06-11
DOI10.1371/journal.pone.0128653
10期:6
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Multidisciplinary Sciences
资助者National Natural Scientific Foundation of China ; Ministry of Science and Technology of China ; National Natural Scientific Foundation of China ; Ministry of Science and Technology of China
研究领域[WOS]Science & Technology - Other Topics
关键词[WOS]LONG-QT SYNDROME ; GATED SODIUM-CHANNELS ; COMMON MOLECULAR DETERMINANTS ; ANTIARRHYTHMIC-DRUG AFFINITY ; LOCAL-ANESTHETIC AFFINITIES ; PAIN DISORDER MUTATIONS ; NA+ CHANNELS ; INACTIVATED STATES ; SLOW INACTIVATION ; SCN5A
英文摘要

Mexiletine and lidocaine are widely used class IB anti-arrhythmic drugs that are considered to act by blocking voltage-gated open sodium currents for treatment of ventricular arrhythmias and relief of pain. To gain mechanistic insights into action of anti-arrhythmics, we characterized biophysical properties of Na(v)1.5 and Na(v)1.7 channels stably expressed in HEK293 cells and compared their use-dependent block in response to mexiletine and lidocaine using whole-cell patch clamp recordings. While the voltage-dependent activation of Na(v)1.5 or Na(v)1.7 was not affected by mexiletine and lidocaine, the steady-state fast and slow inactivation of Na(v)1.5 and Na(v)1.7 were significantly shifted to hyperpolarized direction by either mexiletine or lidocaine in dose-dependent manner. Both mexiletine and lidocaine enhanced the slow component of closed-state inactivation, with mexiletine exerting stronger inhibition on either Na(v)1.5 or Na(v)1.7. The recovery from inactivation of Na(v)1.5 or Na(v)1.7 was significantly prolonged by mexiletine compared to lidocaine. Furthermore, mexiletine displayed a pronounced and prominent use-dependent inhibition of Na(v)1.5 than lidocaine, but not Na(v)1.7 channels. Taken together, our findings demonstrate differential responses to blockade by mexiletine and lidocaine that preferentially affect the gating of Na(v)1.5, as compared to Na(v)1.7; and mexiletine exhibits stronger use-dependent block of Na(v)1.5. The differential gating properties of Na(v)1.5 and Na(v)1.7 in response to mexiletine and lidocaine may help explain the drug effectiveness and advance in new designs of safe and specific sodium channel blockers for treatment of cardiac arrhythmia or pain.

语种英语
所属项目编号81301103 ; 2013CB531302 ; 2014ZX09507
资助者National Natural Scientific Foundation of China ; Ministry of Science and Technology of China ; National Natural Scientific Foundation of China ; Ministry of Science and Technology of China
WOS记录号WOS:000356100900027
引用统计
被引频次:3[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/60258
专题北京大学药学院
作者单位1.Shenzhen Peking Univ, Hong Kong Univ Sci & Technol Med Ctr, Biomed Res Inst, Shenzhen 518036, Peoples R China
2.Chongqing Univ Posts & Telecommun, Coll Comp Sci & Technol, Key Lab Computat Intelligence, Chongqing 400065, Peoples R China
3.Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Dept Mol & Cellular Pharmacol, Beijing 100191, Peoples R China
4.Qingdao Univ, Sch Pharm, Dept Pharmacol, Qingdao 266021, Peoples R China
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GB/T 7714
Wang, Ying,Mi, Jianxun,Lu, Ka,et al. Comparison of Gating Properties and Use-Dependent Block of Na(v)1.5 and Na(v)1.7 Channels by Anti-Arrhythmics Mexiletine and Lidocaine[J]. PLOS ONE,2015,10(6).
APA Wang, Ying,Mi, Jianxun,Lu, Ka,Lu, Yanxin,&Wang, KeWei.(2015).Comparison of Gating Properties and Use-Dependent Block of Na(v)1.5 and Na(v)1.7 Channels by Anti-Arrhythmics Mexiletine and Lidocaine.PLOS ONE,10(6).
MLA Wang, Ying,et al."Comparison of Gating Properties and Use-Dependent Block of Na(v)1.5 and Na(v)1.7 Channels by Anti-Arrhythmics Mexiletine and Lidocaine".PLOS ONE 10.6(2015).
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