K+ CHANNEL INACTIVATION AND ANTIARRHYTHMIC DRUG ACTION

K 通道失活和抗心律失常药物作用

• 批准号: 6390321
• 负责人: Randall L. RASMUSSON
• 金额: $ 24.01万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390321
• 关键词: Xenopus oocyte; antiarrhythmic agent; cardiovascular pharmacology; conformation; ion channel blocker; pharmacokinetics; potassium channel

DESCRIPTION (Adapted from Applicant's Abstract): Recent clinical trials (e.g., CAST and CAST-II) established a cardiotoxic effect of treatment of ventricular arrhythmias with Class I antiarrhythmic agents (Na+ channel blockers). This failure has shifted clinical interest to Class III antiarrhythmic agents (K+ channel blockers). However, antiarrhythmic drugs that block K+ channels vary in selectivity and display conformation specific interactions. Such conformation specific interactions can cause the degree of block of a channel to vary by orders of magnitude depending on the rate, duration and potentials to which the channel is subject. Such conformation dependent binding can be either detrimental or beneficial. This proposal focuses on the relationship between antiarrhythmic drug binding and a particular class of conformational changes, namely C-type inactivation in cardiac K+ channels. C-type inactivation is more widely distributed among cardiac K+ channels than N-type and may be the dominant determinant of such important properties as recovery, K+ sensitivity and drug use-dependent. The goal of this proposal is to elucidate how C-type inactivation can influence the complex patterns of block and use-dependence seen with Class III agents. The central hypothesis is that C-type inactivation involves two conformational changes, closure of the external pore mouth, and closure of the internal pore mouth. Closure of the internal mouth of the channel is proposed to occur through a lipophilic collapse involving the S6 domain. Intracellular lipophilic drug binding promotes this collapse by excluding K+ and increasing the net lipophilic environment. The PI further hypothesizes that the conformational changes in the two regions are not independent but are coupled. The proposed physical and energetic mechanisms will be simulated and tested experimentally to provide a quantitative model of C-type inactivation and antiarrhythmic drug binding. This study will provide a molecular basis for the use dependent properties of a broad class

描述（根据申请人的摘要改编）：最近的临床试验 （例如，铸造和铸造）建立了治疗的心脏毒性作用 具有I类抗心律失常剂（Na+通道）的心室心律不齐 阻滞剂）。 这种失败使临床兴趣转移到了III类 抗心律失常剂（K+通道阻滞剂）。 但是，抗心律失常 该阻断K+通道的选择性各不相同，并显示特定于特定的构象 互动。 这种构象的特定相互作用会导致程度 根据速率的数量级而变化的通道块的块 持续时间和频道对象的潜力。 这样的构象 依赖的结合可能是有害的或有益的。 这个建议 专注于抗心律失常药物结合与A之间的关系 特定类别的构象变化，即C型失活 心脏K+通道。 C型灭活率更广泛地分布 心脏K+通道比N型通道，可能是这种主要决定因素 重要特性作为恢复，K+灵敏度和药物使用依赖性。 该提案的目的是阐明C型灭活如何 影响类别的块和使用依赖性的复杂模式 III代理。 中心假设是C型灭活涉及两个 构象变化，外部孔口的闭合以及闭合 内部毛孔。 闭合通道的内口是 提议通过涉及S6结构域的亲脂性塌陷。 细胞内亲脂性药物结合通过排除K+来促进这种崩溃 并增加净亲脂环境。 PI进一步假设 两个区域的构象变化不是独立的，而是 耦合。 提出的物理和能量机制将是 通过实验进行模拟和测试，以提供定量模型 C型失活和抗心律失常的药物结合。 这项研究会 为广泛类别的使用依赖性提供了分子基础