Polymorphism of cardiac K^+ channel gene and hyperactivity of drugs

心脏K^通道基因多态性与药物亢进

• 批准号: 12670656
• 负责人: KAMIYA Kaichiro
• 金额: $ 1.98万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670656/
• 关键词: Long QT syndrome; Arrhythmias; K+channel; Sudden Cardiac Death; genes; 不整脈死; カリウムチャネル

Acquired long QT syndrome is most caused by block of cardiac HERG K^+ channels by commonly used medications. It is unclear why so many structurally diverse compounds block HERG channels, but this undesirable side effect now is recognized as a major hurdle in the development of new and safe drugs. To determine the structural basis for high-affinity drug block of HERG channels, determined the important residues for drug binding of class III antiarrhythmic agents ; vesnarinone (cardiotonic agent), E-403 1 and dofetilide(a methanesulfonanilide antiarrhythmic drug), MS55 1 (a non-methanesulfonanilide antiarrhythmic drug) and bepridil (multi-channel blocker). We mutated to alanine individual residues of S6 (L646-Y667) and the few residues of the pore helix (L622-V625) predicted to line the channel cavity and inner pore regions based on homology with the solved crystal structure of the KcsA channel (Doyle et al., 1998). Vesnarinone bound to six specific residues within the channel cavity. This result was published in Molecular Pharmacology (Kamiya et al., 2001). In addition, acute application of amiodarone, an antiarrhythmic agent, was found to inhibit HERG current, whereas long-term treatment of amiodarone decreased Iks (Kamiya et al. Circulation 001). Dofetilide caused less block in six channels with Ala missense mutations located in the pore helix (T623A, S624A and V625A) and the S6 domain (G648A, F656A and V659A). These six residues are identical to those reported on MK-499. In addition to these mutants, MS-551 caused less block on 1655A. Bepridil did not block any of S6 mutants except F656A. These results suggest that 1) methanesulfonanilide drugs have common and identical binding sites, 2) class III drugs binds to different residues of HERG channels, hereby producing different pharmacological effects.

获得的长QT综合征最多是由常用药物的心脏HERG K^+通道块引起的。目前尚不清楚为什么如此多的结构上多样化的化合物阻止了HERG频道，但是这种不受欢迎的副作用现在被认为是开发新的和安全药物的主要障碍。为了确定HERG通道高亲和力药物阻滞的结构基础，确定了III类抗心律失常剂的药物结合的重要残基； vesnarinone（心脏毒剂），E-403 1和dofetilide（一种甲烷二烷基抗心律失常药物），MS55 1（一种非甲磺酰基苯胺抗心律失常药物）和BEPRIDIL（多机通道阻滞剂）。我们突变为S6（L646-Y667）的丙氨酸个体残基和孔螺旋的少量残基（L622-V625），预计将基于同源性与KCSA通道的溶液晶体结构（doyle clunnel）（doyle clunnel）对河道腔和内部孔区域进行排列。等，1998）。维斯纳林酮与通道腔内的六个特定残基结合。该结果发表在分子药理学中（Kamiya等，2001）。此外，发现抗心律失常剂胺碘酮的急性施用可抑制HERG电流，而长期治疗氨二酮的IKS降低了IKS（Kamiya等人循环001）。在孔螺旋（T623A，S624A和V625A）和S6域（G648A，F656A和V659A）的六个通道中，多氟乙酯在六个通道中造成较少的阻滞。这六个残留物与MK-499上报道的残留物相同。除了这些突变体外，MS-551在1655a上造成了较小的阻滞。 Bepridil并未阻止除F656a以外的任何S6突变体。这些结果表明，1）甲烷磺烷基药物具有共同且相同的结合位点，2）III类药物与HERG通道的不同残基结合，从而产生不同的药理作用。

项目成果

Kamiya K et al.: "Short and long-term effects of amiodarone on the two components of cardiac delayed rectifier K^+ currents"Circulation. 103. 1317-1324 (2001)

Kamiya K 等人：“胺碘酮对心脏延迟整流 K^ 电流的两个组成部分的短期和长期影响”循环。

Kamiya K,Nishiyama A,Yasui K,Hojo M,Sanguinetti MC,Kodama I.: "Acute and chronic effects of amiodarone on the two components of cardiac delayed rectifier K^+ currents."Circulation.. (in press).

Kamiya K、Nishiyama A、Yasui K、Hojo M、Sanguinetti MC、Kodama I.：“胺碘酮对心脏延迟整流 K^ 电流的两个组成部分的急性和慢性影响。”循环..（印刷中）。

神谷香一郎: "「不整脈の治療の最前線」循環器病への挑戦シリーズXIX"ライフメデイコム. 83 (2001)

Koichiro Kamiya：“心血管疾病‘心律失常治疗前线’挑战系列 XIX”Life Medicom 83 (2001)。

Kamiya K et al.,: "Short and long-term effects of amiodarone on the two components of cardiac delayed rectifier K^+ currents"Circulation. 103. 1317-1324 (2001)

Kamiya K 等人：“胺碘酮对心脏延迟整流 K^ 电流的两个组成部分的短期和长期影响”循环。

Tsuji Y,Tobias O,Kamiya K,Yasui K,Liu W,Lu Z,Kdoama I.: "Pacing-induced heart failure causes a reduction of delayed rectifier potassium currents along with decreases in calcium and transient outward currents in rabbit ventricle."Cardiovascular Research. 4

Tsuji Y、Tobias O、Kamiya K、Yasui K、Liu W、Lu Z、Kdoama I.：“起搏引起的心力衰竭导致延迟整流钾电流减少，同时兔心室中钙和瞬时外向电流减少。”