MOLECULAR MECHANISM FOR AN INHERITED CARDIAC-ARRHYTHMIA
MOLECULAR MECHANISM FOR AN INHERITED CARDIAC-ARRHYTHMIA
复制标题
DOI：
10.1038/376683a0
复制
发表时间：
1995-08-24
期刊：
影响因子：
64.8
通讯作者：
GEORGE, AL
中科院分区：
文献类型：
--
作者：
BENNETT, PB;YAZAWA, K;GEORGE, AL
在先天性长 QT 综合征中，心脏动作电位延长的机制未知 (1,2)，并且使个体容易因室性心律失常而晕厥和猝死 (3)，通过识别多个不同基因座，已证明常染色体显性长 QT 综合征的遗传异质性 (4,5)，最近已发现两个候选基因的相关突变 报道（6,7）。遗传性长 QT (LQT3) 的一种形式与编码人类心脏电压门控钠通道 α 亚基（染色体 3p21 上的 SCN5A）的基因中的突变 (7) (8) 有关。在这里，我们使用重组人心脏钠通道的异源表达来表征这种突变，突变通道在膜去极化过程中显示出持续的内向电流，单通道记录表明突变通道在正常和非失活门控模式之间波动。持续的内向钠电流解释了心脏动作电位的延长，并为这种先天性长 QT 综合征提供了分子机制。
IN the congenital long-QT syndrome, prolongation of the cardiac action potential occurs by an unknown mechanism(1,2) and predisposes individuals to syncope and sudden death as a result of ventricular arrhythmias(3), Genetic heterogeneity has been demonstrated for autosomal dominant long-QT syndrome by the identification of multiple distinct loci(4,5), associated mutations in two candidate genes have recently been reported(6,7). One form of hereditary long QT (LQT3) has been linked to a mutation(7) in the gene encoding the human heart voltage-gated sodium-channel alpha-subunit (SCN5A on chromosome 3p21)(8). Here we characterize this mutation using heterologous expression of recombinant human heart sodium channels, Mutant channels show a sustained inward current during membrane depolarization, Single-channel recordings indicate that mutant channels fluctuate between normal and non-inactivating gating modes. Persistent inward sodium current explains prolongation of cardiac action potentials, and provides a molecular mechanism for this form of congenital long-QT syndrome.