Pharmacological targeting of long QT mutant sodium channels
Pharmacological targeting of long QT mutant sodium channels
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DOI：
10.1172/jci119335
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发表时间：
1997-04-01
影响因子：
15.9
通讯作者：
Bennett, PB
中科院分区：
文献类型：
--
作者：
Wang, DW;Yazawa, K;Bennett, PB
先天性长QT综合征（LOTS）是一种以心肌细胞复极延迟为特征的遗传性疾病，常发生于年轻人，可导致心律失常和猝死。这种疾病的一种形式（LQT3）涉及电压门控心脏钠通道的突变。通过在培养的人细胞中异种表达突变通道来探索靶向抑制LQT缺陷的潜力。动力学和稳态分析表明，对主要带电的伯胺化合物美西汀有明显增强的亲和力。失活状态突变体通道的亲和性与野生型（WT）通道相似（IC50近似于15-20 μ M），但晚开放通道在较低浓度下被抑制（IC50 = 2-3 μ M），导致晚开放优先抑制。靶向突变通道的缺陷行为对这种疾病的治疗干预具有重要意义。这些结果为极低浓度的药物选择性抑制突变表型提供了见解，并表明美西汀同样抑制所有三种已知LQT3突变体的缺陷。
The congenital long QT syndrome (LOTS) is an inherited disorder characterized by a delay in cardiac cellular repolarization leading to cardiac arrhythmias and sudden death often in young people. One form of the disease (LQT3) involves mutations in the voltage-gated cardiac sodium channel. The potential for targeted suppression of the LQT defect was explored by heterologous expression of mutant channels in cultured human cells. Kinetic and steady state analysis revealed an enhanced apparent affinity for the predominantly charged, primary amine compound, mexiletine. The affinity of the mutant channels in the inactivated state was similar to the wild type (WT) channels (IC50 similar to 15-20 mu M), but the late-opening channels were inhibited at significantly lower concentrations (IC50 = 2-3 mu M) causing a preferential suppression of the late openings. The targeting of the defective behavior of the mutant channels has important implications for therapeutic intervention in this disease. The results provide insights for the selective suppression of the mutant phenotype by very low concentrations of drug and indicate that mexiletine equally suppresses the defect in all three known LQT3 mutants.