药学学报

Type	OMIM	Gene	Note
LQTS1	192500	KCNQ1	Encodes the α-subunit of the slow delayed rectifier potassium channel KV7.1 carrying the potassium current IKs (slowly activated delayed rectifier potassium current)
LQTS2	152427	KCNH2	Also known as hERG. Encodes the α-subunit of the rapid delayed rectifier potassium channel KV11.1 carrying the potassium current IKr (rapidly activated delayed rectifier potassium current)
LQTS3	603830	SCN5A	Encodes the α-subunit of the cardiac sodium channel NaV1.5 carrying the sodium current INa
LQTS4	600919	ANK2	Encodes Ankyrin B which anchors the ion channels in the cell. Disputed true association with QT prolongation
LQTS5	176261	KCNE1	Encodes MinK, a potassium channel β-subunit
LQTS6	603796	KCNE2	Encodes MiRP1 (mink related peptide 1), a potassium channel β-subunit
LQTS7	170390	KCNJ2	Encodes inward rectifying potassium current Kir2.1 (inwardly rectifying potassium channel, Kir) carrying the potassium current IK1 (inward rectifier potassium channel). Causes Andersen-Tawil syndrome
LQTS8	601005	CACNA1c	Encodes the α-subunit Cav1.2 of the calcium channel Cav1.2 carrying the calcium current ICaL (L-type calcium channel). Causes Timothy syndrome
LQTS9	611818	CAV3	Encodes Caveolin-3, responsible for forming membrane pouches known as caveolae. Mutations in this gene may increase the late sodium current INa
LQTS10	611819	SCN4B	Encodes the β4-subunit of the cardiac sodium channel
LQTS11	611820	AKAP9	Encodes A-kinase associated protein which interacts with KV7.1.
LQTS12	601017	SNTA1	Encodes syntrophin-α1. Mutations in this gene may increase the late sodium current INa
LQTS13	600734	KCNJ5	Also known as GIRK4, encodes G protein-sensitive inwardly rectifying potassium channels (Kir3.4) which carry the potassium current IK (delayed rectifier potassium current)
LQTS14	616247	CALM1	Encodes calmodulin-1, a calcium-binding messenger protein that interacts with the calcium current ICaL
LQTS15	616249	CALM2	Encodes calmodulin-2, a calcium-binding messenger protein that interacts with the calcium current ICaL
LQTS16	114183	CALM3	Encodes calmodulin-3, a calcium-binding messenger protein that interacts with the calcium current ICaL
Triadin knockout syndrome	615441	TRDN	Encodes triadin gene of chromosome 6q22 which may reduce triadin-mediated negative feedback on the L-type calcium channel, resulting in augmentation of ICaL, prolonged action potential duration
Timothy syndrome	N/A	CACNA1C	Encodes the α-subunit CaV1.2 of the calcium channel Cav1.2 carrying the calcium
Jervell-lange-Nielsen syndrome 1	220400	KCNQ1	Encodes the α-subunit of the slow delayed rectifier potassium channel KV7.1 carrying the potassium current IKs
Jervell-lange-Nielsen syndrome 2	612347	KCNE1	Encodes MinK, a potassium channel β-subunit

Type	OMIM	Gene	Note
LQTS1	192500	KCNQ1	Encodes the α-subunit of the slow delayed rectifier potassium channel KV7.1 carrying the potassium current IKs (slowly activated delayed rectifier potassium current)
LQTS2	152427	KCNH2	Also known as hERG. Encodes the α-subunit of the rapid delayed rectifier potassium channel KV11.1 carrying the potassium current IKr (rapidly activated delayed rectifier potassium current)
LQTS3	603830	SCN5A	Encodes the α-subunit of the cardiac sodium channel NaV1.5 carrying the sodium current INa
LQTS4	600919	ANK2	Encodes Ankyrin B which anchors the ion channels in the cell. Disputed true association with QT prolongation
LQTS5	176261	KCNE1	Encodes MinK, a potassium channel β-subunit
LQTS6	603796	KCNE2	Encodes MiRP1 (mink related peptide 1), a potassium channel β-subunit
LQTS7	170390	KCNJ2	Encodes inward rectifying potassium current Kir2.1 (inwardly rectifying potassium channel, Kir) carrying the potassium current IK1 (inward rectifier potassium channel). Causes Andersen-Tawil syndrome
LQTS8	601005	CACNA1c	Encodes the α-subunit Cav1.2 of the calcium channel Cav1.2 carrying the calcium current ICaL (L-type calcium channel). Causes Timothy syndrome
LQTS9	611818	CAV3	Encodes Caveolin-3, responsible for forming membrane pouches known as caveolae. Mutations in this gene may increase the late sodium current INa
LQTS10	611819	SCN4B	Encodes the β4-subunit of the cardiac sodium channel
LQTS11	611820	AKAP9	Encodes A-kinase associated protein which interacts with KV7.1.
LQTS12	601017	SNTA1	Encodes syntrophin-α1. Mutations in this gene may increase the late sodium current INa
LQTS13	600734	KCNJ5	Also known as GIRK4, encodes G protein-sensitive inwardly rectifying potassium channels (Kir3.4) which carry the potassium current IK (delayed rectifier potassium current)
LQTS14	616247	CALM1	Encodes calmodulin-1, a calcium-binding messenger protein that interacts with the calcium current ICaL
LQTS15	616249	CALM2	Encodes calmodulin-2, a calcium-binding messenger protein that interacts with the calcium current ICaL
LQTS16	114183	CALM3	Encodes calmodulin-3, a calcium-binding messenger protein that interacts with the calcium current ICaL
Triadin knockout syndrome	615441	TRDN	Encodes triadin gene of chromosome 6q22 which may reduce triadin-mediated negative feedback on the L-type calcium channel, resulting in augmentation of ICaL, prolonged action potential duration
Timothy syndrome	N/A	CACNA1C	Encodes the α-subunit CaV1.2 of the calcium channel Cav1.2 carrying the calcium
Jervell-lange-Nielsen syndrome 1	220400	KCNQ1	Encodes the α-subunit of the slow delayed rectifier potassium channel KV7.1 carrying the potassium current IKs
Jervell-lange-Nielsen syndrome 2	612347	KCNE1	Encodes MinK, a potassium channel β-subunit

中药影响hERG钾通道致长-QT综合征机制的研究进展

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张钰浩 , 颜才川 , 王芳 , 李宝馨 ^* , 杨宝峰 ^*

药学学报 | 专题报道：中药心脏安全性评价及合理用于心血管疾病的防治 2019,54(11): 1881-1887

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药学学报 |专题报道：中药心脏安全性评价及合理用于心血管疾病的防治 2019 , 54 (11) : 1881 -1887

中药影响hERG钾通道致长-QT综合征机制的研究进展

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张钰浩, 颜才川, 王芳, 李宝馨^*, 杨宝峰^*

作者信息

哈尔滨医科大学药学院, 黑龙江哈尔滨 150081

通讯作者:

*李宝馨, Tel: 86-451-86671354, E-mail: libx64@hotmail.com;

杨宝峰, yangbf@ems.hrbmu.edu.cn

Advances in research on the mechanism of long-QT syndrome caused by traditional Chinese medicine affecting hERG potassium channel

Yu-hao ZHANG, Cai-chuan YAN, Fang WANG, Bao-xin LI^*, Bao-feng YANG^*

Affiliations

School of Pharmacy, Harbin Medical University, Harbin 150081, China

出版时间: 2019-11-12 doi: 10.16438/j.0513-4870.2019-0369

文章导航

摘要

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药物诱发心脏毒性是近年来备受关注的问题，心脏毒性是药物由市场撤回的主要原因，而长-QT综合征是心脏毒性的重要表现之一，hERG钾通道是药物诱发心律失常和抗心律失常药物作用的重要靶点。中药是我国传统医药，临床使用历史悠久且范围广泛，但中药致多器官毒性仍是有待解决的难题，一些已投入临床使用的中药制剂因潜在的心脏毒性或引起严重的心律失常而被迫从市场撤回。据报道，有50余种临床常用中药产生致心律失常的心脏毒性，其中20余种是通过作用于hERG钾通道致心律失常。因此，寻找药物诱发的长-QT综合征机制及药物干预的调控靶点是当今医药领域的重点研究目标。本文总结了以Ikr/hERG钾通道为主要作用靶点的相关中药诱发长-QT综合征的机制，为临床上合理使用相关中药、避免心脏毒性以及研发药物干预的调控靶点提供理论依据。

关键词

中药 / 心脏毒性 / 长-QT综合征 / hERG

Abstract

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Drug-induced cardiotoxicity is recently a major concern. Cardiotoxicity is the leading cause of drug withdrawal from the market. Long-QT syndrome is one of the most important manifestations of cardiotoxicity. hERG potassium channel is an important target of drug-induced arrhythmia and antiarrhythmia drugs. Traditional Chinese medicine is a traditional medicine in China with a long history and a wide range of clinical use. However, the multi-organ toxicity caused by traditional Chinese medicine is still a problem to be solved. Some traditional Chinese medicines already in clinical use have been withdrawn from the market because of their potential cardiotoxicity or severe arrhythmias. The cardiac toxicity of more than 50 kinds of traditional Chinese medicines causing arrhythmia was reported, while more than 20 of them are induced by affecting on the hERG potassium channels. Therefore, finding out the mechanism of drug-induced long-QT syndrome and the regulatory target of drug intervention is the key research goal in today's medical field. In this paper, we summarized the mechanisms of long-QT syndrome induced by traditional Chinese medicine with Ikr/hERG potassium channel as the main target. It provides a theoretical basis for the rational use of related traditional Chinese medicine in clinical practice, the avoidance of cardiac toxicity and the development of regulatory targets for drug intervention.

Key words

traditional Chinese medicine / cardiotoxicity / long QT syndrome / hERG

引用本文

张钰浩, 颜才川, 王芳, 李宝馨, 杨宝峰. 中药影响hERG钾通道致长-QT综合征机制的研究进展. 药学学报, 2019 , 54 (11) : 1881 -1887 . DOI: 10.16438/j.0513-4870.2019-0369

Yu-hao ZHANG, Cai-chuan YAN, Fang WANG, Bao-xin LI, Bao-feng YANG. Advances in research on the mechanism of long-QT syndrome caused by traditional Chinese medicine affecting hERG potassium channel[J]. Acta Pharmaceutica Sinica, 2019 , 54 (11) : 1881 -1887 . DOI: 10.16438/j.0513-4870.2019-0369

正文

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1 长-QT综合征

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长-QT综合征(long QT syndrome, LQTS)是与心肌离子通道功能异常有关的离子通道病, 亦称QT间期延长综合征, 表现为心肌复极异常、QT间期延长, 心电图上表现为QT间期延长、相对心动过缓、T波异常或明显U波, 可导致除极不均一和早后除极长, 易于发生尖端扭转型室性心动过速(torsade de pointes, TdP), 是导致心源性猝死的危险因素^{[1, 2]}。分为先天遗传性和后天获得性两大类。

1.1 先天性长-QT综合征

先天性长-QT综合征(congenital long QT syndrome, cLQTS)是一种由基因缺陷引起复极异常的遗传性心脏病, 迄今为止, 明确有17种LQTS^[1-3], 主要是钾、钙和钠通道等基因的突变, 导致先天性长-QT综合征(表 1)^[4]。其中hERG钾通道异常所致的LQTS 2型占30%以上。

1.2 获得性长-QT综合征

由药物或心脏疾病等引起的可逆性QT间期延长伴尖端扭转型室性心动过速发作的临床综合征称获得性长-QT综合征(acquired long QT syndrome, acLQTS)^[5]。acLQTS可由药物或疾病如心肌缺血缺氧、心衰等引起^[6], 心肌缺血伴随着缺氧同时诱发QT间期延长已成为临床常见症状^{[7, 8]}, 是心源性猝死一个重要因素。药物诱发的acLQTS与药物抑制心肌细胞膜上的延迟整流钾通道Ikr、促进L型-钙通道及影响钠通道等有关^[9], 其中90%以上是药物抑制Ikr/hERG通道导致^[10]。基于目前心源性猝死发生率升高, 寻找LQTS发生及药物干预的新调控靶点, 进而防治心脏毒性及心源性猝死发生是当今医药领域重点研究目标。

2 hERG通道

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2.1 hERG基因

hERG (human ether-a-go-go related gene)最初是由Warmke等^[11]在人海马cDNA库克隆发现, 后来的研究表明hERG基因在不同组织中均有表达, 且在心脏中高表达。hERG基因位于人类第七号染色体(7p352-36), 全长55 kb, 包含有16个外显子, 由1 159个氨基酸构成, 可以单独构成功能性通道, 其生物物理学特性及药理学特性与Ikr相似^[12]。

2.2 hERG钾通道

离子通道(ion channel)是细胞膜上的一种特殊跨膜整合蛋白, 在脂质双分子层膜上构成亲水性孔道, 且具有选择性地允许适当电荷离子被动通过。离子通道病(ion channelopathy)是指编码离子通道亚单位的基因发生突变或表达异常, 使离子通道的结构或功能异常, 导致机体整体生理功能紊乱, 形成某些先天性的疾病。

hERG编码的钾通道介导的延迟整流钾电流Ikr是复极化过程中主要的钾离子电流, 对调节心肌细胞动作电位2相平台期的终止及3相复极化具有重要意义, 决定着动作电位时程(action potential duration, APD), 是心律失常发生和抗心律失常药物作用的重要靶点^[13]。

2.2.1 hERG钾通道结构

hERG基因编码快速激活延迟整流钾通道Ikr的α亚基^[12], 与minK编码的β亚基及minK相关蛋白MiRP1共同组成快速激活延迟整流钾通道。hERG钾通道是由KCNH2基因编码的4个结构相同的α亚基组成的四聚体, 中间形成离子通道, 每一亚单位包含以下3部分: 6个跨膜的a螺旋片段(S1~S6);羧基端(C端)和氨基端(N端); S5和S6之间的孔区。

S1~S4形成一个电压感受区, 主要参与调节控制hERG的门控特性。S5~S6是离子传导区, 其之间形成的氨基酸链称为P环, 4个α亚基中的S5-P-S6结构区域聚集在一起形成离子通道孔, 具有选择滤过的作用。通道孔及其周围一些位点具有极其重要的作用, 是许多抗心律失常药物的结合位点。S4~S5之间的链接及S6片段的C末端位于通道外口, 形成激活门, 在hERG通道关闭时可以稳定构象。S5-P环之间的链接包含有39个氨基酸, 此区参与通道失活及离子选择过程。C末端含有一个环核苷酸结合域(cyclic-nucleotide-binding domain, cNBD), 对蛋白质转运起到非常重要的作用。N末端在通道的去激活过程中起重要作用, 在N端前135个氨基酸形成一个特殊的与细胞信号传导有关的结构域(Per-Arnt-Sim, PAS), 对蛋白运输和调节hERG通道失活有重要作用。S6结构含有两个特异性芳香族氨基酸:酪氨酸Y652和苯丙氨酸F656。这两个氨基酸的侧链有利于结合亲脂性的碱基, 对药物的芳环结构具有高亲和力, 是大多数hERG阻断药的高亲和力结合位点。

2.2.2 hERG钾通道的门控特性

不同于大多数电压门控钾通道的快失活N-型失活机制, hERG通道的失活属于C-型失活, 是一种慢失活过程。该通道具有其独特特点, 表现在两方面: ①失活比激活快, 在去极化电压下, 这一特性可降低外向电流强度并延长动作电位2期平台期; ②从失活恢复的过程比激活快, 从而影响动作电位3期复极化过程^[13]。

2.3 hERG通道的生物合成

hERG通道蛋白由1 159个氨基酸构成, 首先在内质网(endoplasmic reticulum, ER)中进行翻译, 以未成熟的核糖基化蛋白形式存在, 在分子伴侣的帮助下进行折叠和组装, 一旦蛋白得到正确折叠, 伴侣分子将与蛋白分离, 通道蛋白被外被蛋白Ⅱ (coat protein Ⅱ, COP Ⅱ)囊泡包裹转运至高尔基体, 进行更高秩序的糖基化修饰后被转运至细胞表面^[14], 转变成成熟的糖基化蛋白。hERG通道在内质网中折叠和装配由复杂的伴侣系统的调控。热休克蛋白70 (heat shock protein, Hsp70)参与新合成的hERG蛋白的折叠, 而热休克蛋白90 (heat shock protein, Hsp90)参与后期hERG蛋白的成熟, 并可以抑制错误折叠的蛋白质聚集并促进hERG成熟。

hERG通道的合成过程受到严格的质量控制(quality control, QC)^[15]。在内质网中, hERG蛋白未折叠或发生错误折叠时, 质量控制机制将激活未折叠蛋白反应(unfolded protein response, UPR), 也称为内质网应激反应(endoplasmic reticulum stress, ERS), 防止未正确折叠的蛋白向细胞膜转运。错误折叠的hERG蛋白被Hsp70相互作用蛋白C末端(C-terminal of the Hsp70-interacting protein, CHIP)或泛素标记, 并且在蛋白酶体中通过内质网相关降解(endoplasmic reticulum-associated degradation, ERAD)机制降解。

免疫印迹实验结果分析表明, 未成熟的核糖基化hERG蛋白集中在内质网中, 显示分子质量为135 kDa条带, 而成熟的蛋白在高尔基体及细胞膜上以完全糖基化形式存在, 显示分子质量为155 kDa条带。

2.4 hERG通道与LQTS

2.4.1 hERG与acLQTS

hERG钾通道的孔道中心是相对较大的水充填的腔, 位于选择性滤器和激活闸门以及排列成线的疏水性的氨基酸之间, 在中心腔内位于S6片段有两个芳香族氨基酸Y652、F656, 是高亲和力药物结合的重要位点, 药物与Y652、F656芳香侧链通过共价π-π键相互作用, 结合牢固, 当通道关闭时药物分子易陷在通道内不能释放, 减小Ikr, 诱发acLQTS。

近期应用冰冻电子显微镜测定hERG孔道及中心腔的结构进一步显示, 孔道是开放的, 不规则的中央腔由四个深的疏水口袋围绕, 更证实了药物对hERG敏感作用的本质^[16]。

至目前为止, 156种药物因抑制hERG通道而引起QT间期延长或尖端扭转型室性心动过速, 包括心血管类药物如抗心律失常药物, 非心血管类药物如抗精神病药、抗菌药、抗疟药及抗肿瘤药等(http://www.crediblemeds.org/)^{[17, 18]}。这些药物通过直接影响hERG通道功能, 或影响hERG蛋白转录^[19]、转运(trafficking) ^{[20, 21]}过程而减少膜蛋白表达, 或促进膜蛋白降解^[22]等途径抑制hERG功能, 导致心脏毒性。因此, Ikr/hERG钾通道是产生致命性心律失常及心脏毒性的关键靶点。

2.4.2 hERG与先天性长-QT综合征

由hERG通道突变所致的2型LQTS占所有先天性长-QT综合征30%以上, 其机制大致归结为3点: ① hERG基因内缺失突变导致亚基结构异常而不能与正常的亚基共同装配形成Ikr通道; ② hERG基因错义突变后形成的亚基功能丧失, 与正常亚基共同装配成的Ikr通道功能丧失; ③由于基因突变, 导致蛋白转运定位障碍(trafficking-deficient), 合成的未成熟hERG蛋白被滞留在内质网中, 使细胞膜上功能性Ikr通道的数量减少, 同时降低了Ikr电流密度。

3 中药诱发acLQTS的机制

收起

药物诱发心脏毒性是近年来备受关注的严重问题, 心脏毒性是药物由市场撤回的主要原因, LQTS是心脏毒性的重要表现^[23]。中药经历数千年的临床使用, 在很多疾病的治疗上有着不可替代的疗效和优势, 但随着对中药研发的开展, 一些已投入临床使用的中药制剂因潜在的心脏毒性或引起严重的心律失常而被迫从市场撤回, 近来50余种临床常用中药产生致心律失常的心脏毒性, 包括作者正在进行研究的砒霜、黄连(小檗碱系列物)、吴茱萸次碱和红花黄色素等。

3.1 致心律失常中药

已有文献^[24]报道, 具有致心律失常作用的临床常用中药包括:川草乌、龙胆、砒霜、竹黄、藜芦、雷公藤、人参、生麻黄、细辛、马钱子、夹竹桃、葛根、甘草、首乌、黄连、苦参、丹参和洋地黄等。

3.2 致心律失常中药的成分及其作用机制

已有10余种中药致心律失常机制被阐明, 如川乌、草乌和附子等乌头碱类植物, 其主要毒性成分为乌头碱等多种生物碱。乌头碱通过影响心肌代谢及细胞膜的通透性, 使心肌内钾、钠离子的不平衡, 心肌自律性异常, 房室传导减慢而致心律失常, 且能兴奋迷走神经、抑制窦房结, 减慢心率; 藜芦的有毒成分为原藜芦碱、藜芦苇碱等多种甾体生物碱, 其引起心律失常的作用机制与乌头碱有相似之处, 以窦性心动过缓及房室阻滞较为多见; 人参可使血钾浓度降低, 造成离子紊乱影响心脏传导功能而致心律失常。但目前仍有很多致心律失常中药的机制尚未得到明确地阐释, 是目前开展中药研发亟待解决的难题。

3.3 致心律失常机制与hERG钾通道

药物诱发acLQTS 90%以上通过抑制Ikr/hERG通道导致, 根据文献并结合作者研究结果, 发现有马钱子碱、雷公藤甲素、洋地黄毒苷元、人参皂苷、白藜芦醇、红花黄色素、血根碱和葛根素等20余种中药成分是通过影响hERG钾通道而致心律失常。以下简单列举几种通过抑制hERG钾通道致心律失常的中药成分。

3.3.1 白屈菜碱、白屈菜红碱、血根碱

白屈菜碱及血根碱是传统天然药用植物白屈菜等罂粟科植物的生物碱之一, 其具有显著的hERG钾通道阻断作用^[25]。白屈菜红碱是白屈菜及芸香科植物飞龙掌血的主要有效成分之一, 在表达hERG通道的HEK293细胞中, 白屈菜红碱阻断了hERG电流呈浓度依赖性^[26]。

3.3.2 别隐品碱

别隐品碱是毛茛科唐松草属植物及白屈菜、延胡索等罂粟科植物的主要生物碱之一, 有研究表明别隐品碱能显著延长动作电位时程, 并提出可能是通过影响延迟整流钾电流和内向整流钾电流而发挥作用^[27]。

3.3.3 槐果碱

槐果碱是苦豆草、苦参等豆科植物的生物碱成分之一。结果表明, 槐果碱通过影响通道的失活过程浓度依赖性地抑制hERG钾电流, 使得心肌细胞复极时间延长, 可以改善快速型心律失常^[28]。

3.3.4 葛根素

葛根素是从中药葛根中分离的具有扩冠作用的异黄酮类衍生物, 存在于豆科植物葛及野葛的根部。可以通过抑制hERG钾电流延长复极时间, 抗快速性心律失常^[29]。

3.3.5 槲皮素

槲皮素存在于许多植物的花、叶、果实中, 芦丁等植物中含量较高, 多以甙的形式存在, 属类黄酮衍生物。有研究发现, 在HEK 293细胞中槲皮素能抑制hERG钾通道, 半数抑制浓度(IC₅₀)为11.8 ± 0.9 μmol·L^-1, 最大抑制率(E_max)为82% ± 2%, 首次证明槲皮素是有效的hERG电流阻滞剂^[30]。

3.4 三氧化二砷

3.4.1 砷化合物的药用历史

含砷的化合物作为药物的应用已有2 000多年的历史, 主要用于溃疡、瘟疫、疟疾、梅毒和结核病等多种疾病的治疗。三氧化二砷(As₂O₃)俗称砒霜(arsenic trioxide, ATO), 20世纪70年代, 中国医师张亭栋观察到砒霜对急性早幼粒细胞白血病(acute promyelocytic leukemia, APL)患者有治疗作用, 从那时起, As₂O₃已成为复发性或难治性急性早幼粒细胞白血病治疗的首选用药, 近几十年在世界范围内使用^[31]。但砷化合物导致的高发性心律失常及其严重性极大限制了As₂O₃的临床应用, LQTS是As₂O₃治疗期间观察到的最常见的心律异常疾病。

3.4.2 As₂O₃诱发acLQTS的机制

As₂O₃直接抑制由hERG编码的钾通道亚基携带的复极化钾电流从而诱发acLQTS, 这也是药物致acLQTS的常见机制。有研究表明, As₂O₃通过减少Hsp70、Hsp90与hERG之间的相互作用, 抑制蛋白向膜上转运, 降低hERG通道蛋白表达, 降低心脏钾电流^[32]。并发现转录因子SP1是驱动hERG启动子进行转录的重要因子, 参与调控hERG钾通道^[19], As₂O₃通过Sp1途径影响hERG通道表达诱发acLQTS^[33]。

有研究^{[34, 35]}报道, As₂O₃产生的不良心脏作用与细胞内钙超载和心肌细胞凋亡密切相关, 通过活性氧簇(reactive oxygen species, ROS)的形成、Ca²⁺的增加和蛋白酶caspase-3的激活而介导。As₂O₃诱导心脏纤维化并促进成纤维中转移生长因子β₁的分泌和胶原蛋白的产生, 对hERG通道和钾电流发挥旁分泌抑制作用, 并在心肌细胞中降低hERG和Kir2.1蛋白水平, 从而促进QT间期延长^[36]。进一步的研究发现, 小窝蛋白(caveolin)是一类参与形成微囊小窝(caveolae)的整合膜蛋白, 在多种膜蛋白的内吞转运过程中发挥脚手架的作用, 小窝蛋白-1 (caveolin-1)是小窝蛋白的一种亚型, 与细胞膜上的hERG通道存在相互作用并且可以负调控hERG蛋白的表达, 并参与低钾条件下细胞膜上hERG通道的内吞。此研究发现As₂O₃是通过抑制小窝蛋白-1表达, 促进成熟的hERG蛋白进入溶酶体降解^[22]。

近年发现, 长链非编码RNA (long non-coding RNA, lncRNA)也参与As₂O₃诱发acLQTS的机制。Kcnq1ot1是一种普遍表达的LncRNA, 被认为对心脏发育具有调节作用, 并且在心肌缺血的情况下异常表达。研究发现, As₂O₃在体外和体内均抑制Kcnq1ot1的表达, 表明As₂O₃诱导的acLQTS至少部分是由LncRNA Kcnq1ot1/Kcnq1通路介导的^[37]。根据目前已知研究结果, As₂O₃诱发acLQT的机制可能是通过转运抑制及干扰hERG通道蛋白的表达。

3.5 小檗碱

小檗碱(berberine, BBR), 也称黄连素, 是一种从小檗属和黄连的植物中分离的异喹啉生物碱, 临床主要用于治疗细菌性腹泻和痢疾。

3.5.1 小檗碱的药理作用

在传统的中医药物治疗中, 常用于治疗患有胃肠炎、细菌性痢疾的患者。到目前为止, 随着对其研究的不断深入, 发现该药物还具有多种药理作用, 如降糖、调脂、抗肿瘤及抗心律失常等。小檗碱广泛的药理作用及在心血管方面显著的疗效, 使其具有巨大的应用潜力与价值。

3.5.2 小檗碱类的心脏毒性

一直以来, 小檗碱吸收率低、生物利用度低, 除腹部不适外鲜有其他毒性作用, 被认为是十分安全的药物。但越来越多的报道显示, 小檗碱并不像想象中那样安全。2014年一项研究指出, 小檗碱可能诱导心肌细胞的氧化应激和DNA损伤, 对小鼠产生心脏毒性作用。二氢小檗碱是小檗碱的水解衍生物。药代动力学分析表明, 二氢小檗碱较小檗碱有更好的吸收性和口服生物利用度, 且体内功效优于小檗碱。但也发现二氢小檗碱能抑制hERG通道^[38], 诱发心脏毒性。由于小檗碱的潜在心脏毒性风险, 对于小檗碱心脏毒性的研究愈发必要。

3.5.3 小檗碱对hERG钾通道的作用

已有报道, 小檗碱与hERG通道S6跨膜的两个芳香族氨基酸残基(酪氨酸Tyr652和苯丙氨酸Phe656)相互作用, 急剧阻断非洲爪蟾卵母细胞中的hERG通道。在表达hERG通道的HEK293细胞上小檗碱对hERG电流的IC₅₀为3.1 ± 0.5 μmol·L^-1, 阻断hERG通道并延长动作电位时程^{[39, 40]}。

进一步研究发现, hERG通道的芳香族氨基酸残基Tyr652和Phe656被认为是阻断hERG通道的关键因子^[41], 药物与其相互作用从而发挥阻断作用。小檗碱结合Tyr652和Phe656, 破坏未成熟hERG通道蛋白向细胞膜的正向运输, 增加成熟hERG通道蛋白的降解, 以此两种途径降低hERG通道蛋白表达。但也有可能是小檗碱直接与hERG通道结合, 导致构象改变, 导致异常运输^[38]。

近年来, 临床上应用小檗碱联合抗菌药物针对耐甲氧西林金葡菌的多药耐药菌株进行治疗, 并发现小檗碱与抗生素联合使用会增强对hERG通道的抑制作用^[42]。研究发现小檗碱和克拉霉素联合使用, 是通过加速通道的失活并最终减少hERG通道的瞬时失活时间常数来影响hERG通道动力学, 直接破坏hERG通道门控, 抑制hERG通道电流, 增加诱发acLQTS风险。

3.6 吴茱萸碱类

3.6.1 吴茱萸的用药历史

吴茱萸是一种传统的中药, 始载于《神农本草经》, 在临床应用已有数百年历史。有散寒止痛、降逆止呕、助阳止泻的功效, 用于治疗头痛、胃肠道疾病和月经不适, 或外用于口腔溃疡。吴茱萸碱(evodiamine, Evo)、吴茱萸次碱(rutaecarpine, Rut)、去氢吴茱萸碱(dehydroevodiamine, DHE)及荷蒂芸香胺(hortiamine)是其重要的生物碱成分。

3.6.2 吴茱萸碱类的药理作用

① 对心血管系统的作用:引起心动过缓、低血压和血管舒张。有研究报道^[43], 去氢吴茱萸碱在离体豚鼠心肌细胞中, 电生理学研究表明去氢吴茱萸碱可抑制多个心肌离子电流(如钠电流、钾电流、L型钙电流等), 延长心房和心室动作电位的持续时间; ②抗癌作用; ③抗炎镇痛作用; ④对血栓形成和凝血系统的作用等。

3.6.3 吴茱萸碱类与LQTS

在表达hERG的哺乳动物细胞系中, 通过高效液相色谱法(high performance liquid chromatography, HPLC)分析、膜片钳研究及在线和离线光谱分析, 发现去氢吴茱萸碱与荷蒂芸香胺可以阻断hERG通道。通过分子对接技术, 发现去氢吴茱萸碱与hERG的中心腔结合, 与Y652形成疏水相互作用, 与F656形成π-π堆积。数据表明去氢吴茱萸碱的吲哚环能在Y652和F656之间以夹心型方式排列, 从而允许π-π堆积与两种氨基酸相互作用。证实DHE通过结合hERG S6区段上两种已知氨基酸(Y652, F656)阻断hERG通道^[44]。体外和体内研究揭示了去氢吴茱萸碱与荷蒂芸香胺有强烈的致心律失常作用, 呈剂量依赖性但在高剂量(0.5 mg·kg^-1)时具有自限性。

近期作者应用分子对接技术预测出吴茱萸次碱也可与hERG通道结合, 并抑制通道电流诱发acLQTS。目前吴茱萸碱类抑制hERG通道致acLQTS的机制尚未阐明, 有待进一步研究。

4 总结与展望

收起

综上所述, 传统的中药虽然在治疗某些特定疾病具有良好的疗效和优势, 但其易致获得性长-QT综合征的潜在风险提示在临床上应合理、谨慎地使用这些中药, 预防其心脏毒性等不良反应。实验研究方面, 从多角度、多靶点阐明了中药致获得性长-QT综合征的分子机制, 无论是动物实验还是细胞研究均取得较大进展, 为探索中药治疗靶点及研究创新型中药奠定理论基础。在这些研究成果中, hERG钾离子通道是介导中药诱发的获得性长-QT综合征的关键靶点。药物如小檗碱等因其自身的结构特性和理化性质, 可以直接结合hERG通道的某些氨基酸片段从而导致通道阻塞; 三氧化二砷等还能够改变细胞内的信号传导, 最终导致hERG钾离子通道表达障碍, 引起获得性长-QT综合征。

我国中药资源丰富且中医理论和实践历史悠久, 充分利用中药及其组分在临床应用方面的优势, 并且避免其产生不良反应是现代医药学发展的重要任务。在诸多药物不良反应中, 药物的心脏毒性是较为突出的问题之一。因此, 明确中药或其组分诱发的心脏毒性, 特别是药物诱发的hERG钾离子通道相关的获得性LQTS; 探索通过药物改构、合理用药及联合用药等方法降低药物的毒副作用是目前临床和基础研究的重点。总之, 探索和总结中药诱发的acLQTS的分子机制及研发靶向干预的药物能够有效降低其心脏毒性, 进一步拓展其广泛的临床应用前景。

基金

收起

国家自然科学基金资助项目(81673636)

参考文献

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文献

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参考文献引证文献

排序方式：

[1]

Abriel

, Zaklyazminskaya

. Cardiac channelopathies: genetic and molecular mechanisms[J]. Gene, 2013, 517: 1-11.

https://doi.org/10.1016/j.gene.2012.12.061

[2]

Garcia-Elias

, Benito

. Ion channel disorders and sudden cardiac death[J]. Int J Mol Sci, 2018, 19: 692.

https://doi.org/10.3390/ijms19030692

[3]

Vaidyanathan

, Reilly

, Eckhardt

et al . Caveolin-3 microdomain: arrhythmia implications for potassium inward rectifier and cardiac sodium channel[J]. Front Physiol, 2018, 9: 1548.

https://doi.org/10.3389/fphys.2018.01548

[4]

Giudicessi

, Wilde

AAM

, Ackerman

et al . The genetic architecture of long QT syndrome: a critical reappraisal[J]. Trends Cardiovasc Med, 2018, 28: 453-464.

https://doi.org/10.1016/j.tcm.2018.03.003

[5]

Choy

, Lang

, Chomsky

et al . Normalization of acquired QT prolongation in humans by intravenous potassium[J]. Circulation, 1997, 96: 2149-2154.

https://doi.org/10.1161/01.CIR.96.7.2149

[6]

Roden

, Viswanathan

. Genetics of acquired long QT syndrome[J]. J Clin Invest, 2005, 115: 2025-2032.

https://doi.org/10.1172/JCI25539

[7]

Kenigsberg

, Khanal

, Kowalski

et al . Prolongation of the QTc interval is seen uniformly during early transmural ischemia[J]. J Am Coll Cardiol, 2007, 49: 1299-1305.

https://doi.org/10.1016/j.jacc.2006.11.035

[8]

Shimoda

, Polak

. Hypoxia. 4. Hypoxia and ion channel function[J]. Am J Physiol Cell Physiol, 2011, 300: C951-C967.

https://doi.org/10.1152/ajpcell.00512.2010

[9]

Huang

, Pugsley

, Fermini

et al . Cardiac voltage-gated ion channels in safety pharmacology: review of the landscape leading to the CiPA initiative[J]. J Pharmacol Toxicol Methods, 2017, 87: 11-23.

https://doi.org/10.1016/j.vascn.2017.04.002

[10]

Lee

, Windley

, Vandenberg

et al . In vitro and in silico risk assessment in acquired long QT syndrome: the devil is in the details[J]. Front Physiol, 2017, 8: 934.

https://doi.org/10.3389/fphys.2017.00934

[11]

Warmke

, Ganetzky

. A family of potassium channel genes related to EAG in drosophila and mammals[J]. Proc Natl Acad Sci USA, 1994, 91: 3438-3442.

https://doi.org/10.1073/pnas.91.8.3438

[12]

Sanguinetti

, Jiang

, Curran

et al . A mechanistic link between an inherited and an acquired cardiac arrhythmia: hERG encodes the Ikr potassium channel[J]. Cell, 1995, 81: 299-307.

https://doi.org/10.1016/0092-8674(95)90340-2

[13]

Sanguinetti

, Tristani-Firouzi M . hERG potassium channels and cardiac arrhythmia[J]. Nature, 2006, 440: 463-469.

https://doi.org/10.1038/nature04710

[14]

Smith

, McBride

, Nataraj

et al . Trafficking-deficient hERG K⁺ channels linked to long QT syndrome are regulated by a microtubule-dependent quality control compartment in the ER[J]. Am J Physiol Cell Physiol, 2011, 301: 75-85.

https://doi.org/10.1152/ajpcell.00494.2010

[15]

Foo

, Williamson

, Young

et al . hERG quality control and the long QT syndrome[J]. J Physiol, 2016, 594: 2469-2481.

https://doi.org/10.1113/JP270531

[16]

Wang

, MacKinnon

. Cryo-EM structure of the open human ether-à-go-go-related K⁺ channel hERG[J]. Cell, 2017, 169: 422-430.

https://doi.org/10.1016/j.cell.2017.03.048

[17]

Vandenberg

, Perry

, Perrin

et al . hERG K⁺ channels: structure, function and clinical significance[J]. Physiol Rev, 2012, 92: 1393-1478.

https://doi.org/10.1152/physrev.00036.2011

[18]

Kalyaanamoorthy

, Barakat

. Development of safe drugs: the hERG challenge[J]. Med Res Rev, 2018, 38: 525-555.

https://doi.org/10.1002/med.21445

[19]

Zhang

, Dong

, Jin

et al . Arsenic trioxide-induced hERG K⁺ channel deficiency can be rescued by matrine and oxymatrine through up-regulating transcription factor Sp1 expression[J]. Biochem Pharmacol, 2013, 85: 59-68.

https://doi.org/10.1016/j.bcp.2012.09.002

[20]

Dennis

, Wang

, Wan

et al . hERG channel trafficking: novel targets in drug-induced long QT syndrome[J]. Biochem Soc Trans, 2007, 35: 1060-1063.

https://doi.org/10.1042/BST0351060

[21]

de Git

, de Boer

, Vos

et al . Cardiac ion channel trafficking defects and drugs[J]. Pharmacol Ther, 2013, 139: 24-31.

https://doi.org/10.1016/j.pharmthera.2013.03.008

[22]

Yan

, Feng

, Shi

et al . Mechanism of As₂O₃-induced action potential prolongation and using hiPS-CMs to evaluate therescue efficacy of drugs with different rescue mechanism[J]. Toxicol Sci, 2017, 158: 379-390.

https://doi.org/10.1093/toxsci/kfx098

[23]

Cai

, Guo

, Zhou

et al . Deep learning-based prediction of drug-induced cardiotoxicity[J]. J Chem Inf Model, 2019, 59: 1073-1084.

https://doi.org/10.1021/acs.jcim.8b00769

[24]

Liu

, Li

, Wang

et al . Advances in research on arrhythmogenic Chinese medicine[J]. Med Inform (医学信息), 2014, 27: 648-649.

[25]

Orvos

, Virág

, Tálosi

et al . Effects of Chelidonium majus extracts and major alkaloids on hERG potassium channels and on dog cardiac action potential-a safety approach[J]. Fitoterapia, 2015, 100: 156-165.

https://doi.org/10.1016/j.fitote.2014.11.023

[26]

Harmati

, Papp

, Szentandrássy

et al . Effects of the PKC inhibitors chelerythrine and bisindolylmaleimide I (GF109203X) on delayed rectifier K⁺ currents[J]. Naunyn Schmiedebergs Arch Pharmacol, 2011, 383: 141-148.

https://doi.org/10.1007/s00210-010-0584-8

[27]

, Wang

, Cheng

et al . Anti-arrhythmia effect of crypto-alkali and its effect on action potential[J]. Chin J Mult Organ Dis Elder (中华老年多器官疾病杂志), 2005, 4: 123-126.

[28]

Zhao

, Gu

, Qi

et al . Comparative effects of sophocarpine and sophoridine on hERG K⁺ channel[J]. Eur J Pharmacol, 2009, 607: 15-22.

https://doi.org/10.1016/j.ejphar.2009.02.013

[29]

Chen

, Huang

, Wei

et al . Effect of puerarin on action potential and delayed rectifier potassium current of guinea pig papillary muscle[J]. Chin Pharm J (中国药学杂志), 2006, 41: 747-749.

[30]

Sun

, Xu

, Xue

et al . Characterization and structure-activity relationship of natural flavonoids as hERG K⁺ channel modulators[J]. Int Immunopharmacol, 2017, 45: 187-193.

https://doi.org/10.1016/j.intimp.2017.02.012

[31]

Cyranoski

. Arsenic patent keeps drug for rare cancer out of reach of many[J]. Nat Med, 2007, 13: 1005.

https://doi.org/10.1038/nm0907-1005

[32]

Shinnawi

, Gepstein

. iPCS cell modeling of inherited cardiac arrhythmias[J]. Curr Treat Opt Cardiovascular Med, 2014, 16: 331.

https://doi.org/10.1007/s11936-014-0331-4

[33]

Dong

, Shi

, Feng

et al . (-)-Epicatechin rescues the As₂O₃-induced hERG K⁺ channel deficiency possibly through upregulating transcription factor SP1 expression[J]. J Biochem Mol Toxicol, 2017, 31: e21966.

https://doi.org/10.1002/jbt.21966

[34]

Zhao

, Feng

, Shen

et al . Arsenic trioxide-induced apoptosis in h9c2 cardiomyocytes: implications in cardiotoxicity[J]. Basic Clin Pharmacol Toxicol, 2008, 102: 419-425.

https://doi.org/10.1111/j.1742-7843.2007.00150.x

[35]

Zhao

, Li

, Yang

et al . Resveratrol protects against arsenic trioxide-induced cardiotoxicity in vitro and in vivo[J]. Br J Pharmacol, 2008, 154: 105-113.

https://doi.org/10.1038/bjp.2008.81

[36]

Chu

, Li

, Qu

et al . Arsenic-induced interstitial myocardial fibrosis reveals a new insight into drug-induced long QT syndrome[J]. Cardiovascular Res, 2012, 96: 90-98.

https://doi.org/10.1093/cvr/cvs230

[37]

Jiang

, Du

, Chu

et al . Downregulation of long non-coding RNA Kcnq1ot1: an important mechanism of arsenic trioxide-induced long QT syndrome[J]. Cell Physiol Biochem, 2018, 45: 192-202.

https://doi.org/10.1159/000486357

[38]

, Lv

, Fang

et al . Inhibitory effects and mechanism of dihydroberberine on hERG channels expressed in HEK293 cells[J]. PLoS One, 2017, 12: e0181823.

https://doi.org/10.1371/journal.pone.0181823

[39]

Zhang

, Zhi

, Huang

et al . Berberine induces hERG channel deficiency through trafficking inhibition[J]. Cell Physiol Biochem, 2014, 34: 691-702.

https://doi.org/10.1159/000363034

[40]

, Yang

, Zhou

et al . Inhibition of berberine on IK1, IK and hERG channels in cardiomyocytes[J]. Chin Pharm J (中国药学杂志), 2001, 36: 33-39.

[41]

Zhang

, Colenso

, El

Harchi A

et al . Interactions between amiodarone and the hERG potassium channel pore determined with mutagenesis and in silico docking[J]. Biochem Pharmacol, 2016, 113: 24-35.

https://doi.org/10.1016/j.bcp.2016.05.013

[42]

Zhi

, Feng

, Sun

et al . The enhancement of cardiac toxicity by concomitant administration of Berberine and macrolides[J]. Eur J Pharm Sci, 2015, 76: 149-155.

https://doi.org/10.1016/j.ejps.2015.05.009

[43]

Lin

, Wang

, Shen

et al . Advances in pharmacological effects of Wujing alkaloids on cardiovascular[J]. Chin J Clin Res(中国临床研究), 2015, 28: 1392-1393.

[44]

Baburin

, Varkevisser

, Schramm

et al . Dehydroevodiamine and hortiamine, alkaloids from the traditional Chinese herbal drug Evodia rutaecarpa, are I Kr blockers with proarrhythmic effects in vitro and in vivo[J]. Pharmacol Res, 2018, 131: 150-163.

https://doi.org/10.1016/j.phrs.2018.02.024

2019年第54卷第11期

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doi: 10.16438/j.0513-4870.2019-0369

接收时间：2019-05-14
首发时间：2026-01-26
出版时间：2019-11-12

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收稿日期：2019-05-14
修回日期：2019-08-19

基金

国家自然科学基金资助项目(81673636)

作者信息

哈尔滨医科大学药学院, 黑龙江哈尔滨 150081

通讯作者:

*李宝馨, Tel: 86-451-86671354, E-mail: libx64@hotmail.com;

杨宝峰, yangbf@ems.hrbmu.edu.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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TxT

Type	OMIM	Gene	Note
LQTS1	192500	KCNQ1	Encodes the α-subunit of the slow delayed rectifier potassium channel KV7.1 carrying the potassium current IKs (slowly activated delayed rectifier potassium current)
LQTS2	152427	KCNH2	Also known as hERG. Encodes the α-subunit of the rapid delayed rectifier potassium channel KV11.1 carrying the potassium current IKr (rapidly activated delayed rectifier potassium current)
LQTS3	603830	SCN5A	Encodes the α-subunit of the cardiac sodium channel NaV1.5 carrying the sodium current INa
LQTS4	600919	ANK2	Encodes Ankyrin B which anchors the ion channels in the cell. Disputed true association with QT prolongation
LQTS5	176261	KCNE1	Encodes MinK, a potassium channel β-subunit
LQTS6	603796	KCNE2	Encodes MiRP1 (mink related peptide 1), a potassium channel β-subunit
LQTS7	170390	KCNJ2	Encodes inward rectifying potassium current Kir2.1 (inwardly rectifying potassium channel, Kir) carrying the potassium current IK1 (inward rectifier potassium channel). Causes Andersen-Tawil syndrome
LQTS8	601005	CACNA1c	Encodes the α-subunit Cav1.2 of the calcium channel Cav1.2 carrying the calcium current ICaL (L-type calcium channel). Causes Timothy syndrome
LQTS9	611818	CAV3	Encodes Caveolin-3, responsible for forming membrane pouches known as caveolae. Mutations in this gene may increase the late sodium current INa
LQTS10	611819	SCN4B	Encodes the β4-subunit of the cardiac sodium channel
LQTS11	611820	AKAP9	Encodes A-kinase associated protein which interacts with KV7.1.
LQTS12	601017	SNTA1	Encodes syntrophin-α1. Mutations in this gene may increase the late sodium current INa
LQTS13	600734	KCNJ5	Also known as GIRK4, encodes G protein-sensitive inwardly rectifying potassium channels (Kir3.4) which carry the potassium current IK (delayed rectifier potassium current)
LQTS14	616247	CALM1	Encodes calmodulin-1, a calcium-binding messenger protein that interacts with the calcium current ICaL
LQTS15	616249	CALM2	Encodes calmodulin-2, a calcium-binding messenger protein that interacts with the calcium current ICaL
LQTS16	114183	CALM3	Encodes calmodulin-3, a calcium-binding messenger protein that interacts with the calcium current ICaL
Triadin knockout syndrome	615441	TRDN	Encodes triadin gene of chromosome 6q22 which may reduce triadin-mediated negative feedback on the L-type calcium channel, resulting in augmentation of ICaL, prolonged action potential duration
Timothy syndrome	N/A	CACNA1C	Encodes the α-subunit CaV1.2 of the calcium channel Cav1.2 carrying the calcium
Jervell-lange-Nielsen syndrome 1	220400	KCNQ1	Encodes the α-subunit of the slow delayed rectifier potassium channel KV7.1 carrying the potassium current IKs
Jervell-lange-Nielsen syndrome 2	612347	KCNE1	Encodes MinK, a potassium channel β-subunit

Type

OMIM

Gene

Note

LQTS1

192500

KCNQ1

Encodes the α-subunit of the slow delayed rectifier potassium channel KV7.1 carrying the potassium
current IKs (slowly activated delayed rectifier potassium current)

LQTS2

152427

KCNH2

Also known as hERG. Encodes the α-subunit of the rapid delayed rectifier potassium channel KV11.1 carrying the potassium current IKr (rapidly activated delayed rectifier potassium current)

LQTS3

603830

SCN5A

Encodes the α-subunit of the cardiac sodium channel NaV1.5 carrying the sodium current INa

LQTS4

600919

ANK2

Encodes Ankyrin B which anchors the ion channels in the cell. Disputed true association with QT
prolongation

LQTS5

176261

KCNE1

Encodes MinK, a potassium channel β-subunit

LQTS6

603796

KCNE2

Encodes MiRP1 (mink related peptide 1), a potassium channel β-subunit

LQTS7

170390

KCNJ2

Encodes inward rectifying potassium current Kir2.1 (inwardly rectifying potassium channel, Kir) carrying the potassium current IK1 (inward rectifier potassium channel). Causes Andersen-Tawil syndrome

LQTS8

601005

CACNA1c

Encodes the α-subunit Cav1.2 of the calcium channel Cav1.2 carrying the calcium current ICaL (L-type calcium channel). Causes Timothy syndrome

LQTS9

611818

CAV3

Encodes Caveolin-3, responsible for forming membrane pouches known as caveolae. Mutations in this gene may increase the late sodium current INa

LQTS10

611819

SCN4B

Encodes the β4-subunit of the cardiac sodium channel

LQTS11

611820

AKAP9

Encodes A-kinase associated protein which interacts with KV7.1.

LQTS12

601017

SNTA1

Encodes syntrophin-α1. Mutations in this gene may increase the late sodium current INa

LQTS13

600734

KCNJ5

Also known as GIRK4, encodes G protein-sensitive inwardly rectifying potassium channels (Kir3.4) which carry the potassium current IK (delayed rectifier potassium current)

LQTS14

616247

CALM1

Encodes calmodulin-1, a calcium-binding messenger protein that interacts with the calcium current ICaL

LQTS15

616249

CALM2

Encodes calmodulin-2, a calcium-binding messenger protein that interacts with the calcium current ICaL

LQTS16

114183

CALM3

Encodes calmodulin-3, a calcium-binding messenger protein that interacts with the calcium current ICaL

Triadin knockout syndrome

615441

TRDN

Encodes triadin gene of chromosome 6q22 which may reduce triadin-mediated negative feedback on the L-type calcium channel, resulting in augmentation of ICaL, prolonged action potential duration

Timothy syndrome

N/A

CACNA1C

Encodes the α-subunit CaV1.2 of the calcium channel Cav1.2 carrying the calcium

Jervell-lange-Nielsen syndrome 1

220400

KCNQ1

Encodes the α-subunit of the slow delayed rectifier potassium channel KV7.1 carrying the potassium
current IKs

Jervell-lange-Nielsen syndrome 2

612347

KCNE1

Encodes MinK, a potassium channel β-subunit