Molecular physiology and pharmacology of HERG - Single-channel currents and block by dofetilide
Molecular physiology and pharmacology of HERG - Single-channel currents and block by dofetilide
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DOI：
10.1161/01.cir.94.10.2572
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发表时间：
1996-11-15
期刊：
影响因子：
37.8
通讯作者：
Brown, AM
中科院分区：
文献类型：
--
作者：
Kiehn, J;Lacerda, AE;Brown, AM
背景人类ether-a-go-go-related基因（HERG）是遗传性长QT综合征的一个位点。一种假设是HERG产生复极化心脏钾电流I-Kr，结果是HERG突变通过降低I-Kr延长QT间期。HERG的基本属性是未知的，并作为一个测试的假设，HERG产生I-Kr，我们比较了它们的基本properties.Methods和Results我们注入HERC cRNA到非洲爪蟾卵母细胞和测量电流从单通道或电流方差的噪声所产生的合奏记录从宏补丁的通道。单通道电导依赖于细胞外钾离子浓度（[K]（o））。在生理[K]（o）下，它为2皮西门子（pS），在100 mmol/L [K]（o）下，它为10 pS。在-100 mV时，以平均持续时间为26 Ins的爆发形式出现开放。平均开放时间为3.2 ms，闭合时间为1.0 ms和26 ms。在切除的宏斑中，HERG电流被III类抗心律失常药物多非利特阻断，IC 50为35 nmol/L。多非利特阻滞是缓慢的，大大衰减在正电位HERG rectifies.Conclusions HERG和I-Kr的微观生理学是相似的，与HERG是I-Kr的一个重要组成部分一致。药理学也相似：多非利特似乎主要阻断活化通道，对封闭和失活通道的亲和力低得多。
Background The human ether-a-go-go-related gene (HERG) is one locus for the hereditary long QT syndrome. A hypothesis is that HERG produces the repolarizing cardiac potassium current I-Kr, with the consequence that mutations in HERG prolong the QT interval by reducing I-Kr. The elementary properties of HERG are unknown, and as a test of the hypothesis that HERG produces I-Kr, we compared their elementary properties.Methods and Results We injected HERC cRNA into Xenopus oocytes and measured currents from single channels or current variance from the noise produced by ensembles of channels recorded from macro patches. Single-channel conductance was dependent on the extracellular potassium concentration ([K](o)). At physiological [K](o), it was 2 picosiemens (pS), and at 100 mmol/L [K](o), it was 10 pS. Openings occurred in bursts with a mean duration of 26 Ins at -100 mV. Mean open time was 3.2 ms and closed times were 1.0 and 26 ms. In excised macro patches, HERG currents were blocked by the class III antiarrhythmic drug dofetilide, with an IC50 of 35 nmol/L. Dofetilide block was slow and greatly attenuated at positive potentials at which HERG rectifies.Conclusions The microscopic physiology of HERG and I-Kr is similar, consistent with HERG being an important component of I-Kr. The pharmacology is also similar: dofetilide appears to primarily block activated channels and has a much lower affinity for closed and inactivated channels.