Bennett P B, Yazawa K, Makita N, George A L
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Nature. 1995 Aug 24;376(6542):683-5. doi: 10.1038/376683a0.
In the congenital long-QT syndrome, prolongation of the cardiac action potential occurs by an unknown mechanism and predisposes individuals to syncope and sudden death as a result of ventricular arrhythmias. Genetic heterogeneity has been demonstrated for autosomal dominant long-QT syndrome by the identification of multiple distinct loci, and associated mutations in two candidate genes have recently been reported. One form of hereditary long QT (LQT3) has been linked to a mutation in the gene encoding the human heart voltage-gated sodium-channel alpha-subunit (SCN5A on chromosome 3p21). 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.
在先天性长QT综合征中，心脏动作电位延长的机制尚不清楚，这使得个体易因室性心律失常而发生晕厥和猝死。通过鉴定多个不同的基因座，已证实常染色体显性遗传长QT综合征存在遗传异质性，最近还报道了两个候选基因中的相关突变。一种遗传性长QT（LQT3）形式与编码人心脏电压门控钠通道α亚基（位于3号染色体p21上的SCN5A）的基因突变有关。在此，我们利用重组人心脏钠通道的异源表达对该突变进行了表征。突变通道在膜去极化期间显示出持续的内向电流。单通道记录表明，突变通道在正常门控模式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综合征形式提供了分子机制。
