Insights into the molecular mechanisms of bradycardia-triggered arrhythmias in long QT-3 syndrome.
Insights into the molecular mechanisms of bradycardia-triggered arrhythmias in long QT-3 syndrome.
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DOI：
10.1172/jci15928
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发表时间：
2002-11
期刊：
影响因子：
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通讯作者：
C. Clancy;M. Tateyama;R. Kass
中科院分区：
文献类型：
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作者：
C. Clancy;M. Tateyama;R. Kass
先天性长QT综合征是一种罕见的疾病，其心电图QT间期延长是由于心室复极功能障碍所致。变异3(LQT-3)与SCN5A的突变有关，SCN5A是心脏Na(+)通道阿尔法亚单位的编码基因。当心率缓慢时，LQT-3突变携带者在休息时更有可能发生心律失常。几个LQT-3Na(+)通道突变通过促进Na(+)通道门控模式发挥其有害作用，其中一部分通道无法失活。这种门控模式被称为“猝发”，导致持续的宏观内向钠(+)通道电流(I(SU))，这可以延迟复极并延长QT间期。然而，在单通道水平上，i(SU)的心率依赖机制尚未解决。我们使用实验和理论框架研究了LQT-3突变体(Y1795C)，以阐明I(SU)速率依赖的分子机制。我们的结果表明，突变导致的突变通道破裂时间长度的变化，而不是它们破裂的容易程度，决定了I(SU)反向心率依赖。我们的结果表明，突变导致的突变通道破裂时间长度的变化，而不是它们破裂的容易程度，决定了I(SU)反向心率依赖。这些结果将突变引起的Na+通道门控模式转变与心率相关的细胞电活动变化联系在一起，这是LQT-3关键临床表型的基础。
Congenital long QT syndrome is a rare disease in which the electrocardiogram QT interval is prolonged due to dysfunctional ventricular repolarization. Variant 3 (LQT-3) is associated with mutations in SCN5A, the gene coding for the heart Na(+) channel alpha subunit. Arrhythmias in LQT-3 mutation carriers are more likely to occur at rest, when heart rate is slow. Several LQT-3 Na(+) channel mutations exert their deleterious effects by promoting a mode of Na(+) channel gating wherein a fraction of channels fails to inactivate. This gating mode, termed "bursting, " results in sustained macroscopic inward Na(+) channel current (I(sus)), which can delay repolarization and prolong the QT interval. However, the mechanism of heart-rate dependence of I(sus) has been unresolved at the single-channel level. We investigate an LQT-3 mutant (Y1795C) using experimental and theoretical frameworks to elucidate the molecular mechanism of I(sus) rate dependence. Our results indicate that mutation-induced changes in the length of time mutant channels spend bursting, rather than how readily they burst, determines I(sus) inverse heart-rate dependence. Our results indicate that mutation-induced changes in the length of time mutant channels spend bursting, rather than how readily they burst, determines I(sus) inverse heart-rate dependence. These results link mutation-induced changes in Na+ channel gating mode transitions to heart rate-dependent changes in cellular electrical activity underlying a key LQT-3 clinical phenotype.