An R H, Bangalore R, Rosero S Z, Kass R S
Department of Physiology, University of Rochester, School of Medicine, NY, USA.
Circ Res. 1996 Jul;79(1):103-8. doi: 10.1161/01.res.79.1.103.
In transiently transfected mammalian cells we have identified pharmacological consequences of a naturally occurring deletion mutation, delta KPQ, of the human heart Na+ channel alpha subunit that previously has been linked to one form of the long QT syndrome, an inherited heart disease. Our results show that the Class IB antiarrhythmic agent lidocaine blocks maintained inward current through and slows recovery from inactivation of delta KPQ-encoded Na+ channels. Block is greater for maintained than for peak current. Because incomplete inactivation of mutant Na+ channels is now thought to underlie the prolonged ventricular action potential, which is the phenotype of this disease, and we find that the delta KPQ mutation speeds the recovery from inactivation of drug-free mutant channels, our results provide evidence, for the first time, that clinically relevant dysfunctional properties of an ion channel can be selectively targeted on the basis of the molecular properties conferred on the channel by an inherited genetic disorder.
在瞬时转染的哺乳动物细胞中，我们已经确定了人类心脏钠通道α亚基自然发生的缺失突变ΔKPQ的药理学后果，该突变先前已与长QT综合征（一种遗传性心脏病）的一种形式相关联。我们的结果表明，I B类抗心律失常药物利多卡因可阻断通过ΔKPQ编码的钠通道的持续内向电流，并减缓失活后的恢复。对持续电流的阻断作用大于对峰值电流的阻断作用。由于现在认为突变钠通道的不完全失活是该疾病表型（即延长的心室动作电位）的基础，并且我们发现ΔKPQ突变加快了无药物突变通道失活后的恢复，因此我们的结果首次提供了证据，表明离子通道的临床相关功能失调特性可以基于遗传性疾病赋予通道的分子特性进行选择性靶向。
