Channel openings are necessary but not sufficient for use-dependent block of cardiac Na(+) channels by flecainide: evidence from the analysis of disease-linked mutations.
Channel openings are necessary but not sufficient for use-dependent block of cardiac Na(+) channels by flecainide: evidence from the analysis of disease-linked mutations.
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DOI：
10.1085/jgp.20028558
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发表时间：
2002-07
影响因子：
3.8
通讯作者：
Kass, Robert S
中科院分区：
文献类型：
--
作者：
Liu, Huajun;Tateyama, Michihiro;Clancy, Colleen E;Abriel, Hugues;Kass, Robert S
Na+通道阻滞剂如氟卡尼在诊断和治疗由SCN 5A（编码心脏电压门控Na+通道α亚基的基因）遗传突变引起的两种临床综合征中发现了新的用途。Brugada综合征（BrS）和长QT综合征的LQT-3变体是由疾病相关的SCN 5A突变引起的，这些突变改变了通道的功能和药理学特性。在这里，我们探索了一组与BrS和LQT-3相关的SCN 5A突变，以确定对Na+通道阻滞剂氟卡尼的不同反应的疾病修饰通道特性。我们专注于氟卡尼阻滞，这种阻滞是随着重复性通道活动而发展的，即所谓的使用依赖性阻滞（UDB）。我们的研究结果表明，突变引起的变化的电压依赖性通道的可用性（失活）可能作为氟卡尼块的决定因素。数据进一步表明，氟卡尼的UDB需要通道开放，但不太可能是由于开放通道阻滞。相反，氟卡尼似乎与去极化诱导的通道开放后的失活状态相互作用，而突变诱导的通道失活变化将改变氟卡尼阻滞，与突变相关的疾病无关。氟卡尼阻断与这些罕见疾病相关的突变通道的分析为药物作用的分子决定因素提供了新的见解。
Na+ channel blockers such as flecainide have found renewed usefulness in the diagnosis and treatment of two clinical syndromes arising from inherited mutations in SCN5A, the gene encoding the α subunit of the cardiac voltage–gated Na+ channel. The Brugada syndrome (BrS) and the LQT-3 variant of the Long QT syndrome are caused by disease-linked SCN5A mutations that act to change functional and pharmacological properties of the channel. Here we have explored a set of SCN5A mutations linked both to BrS and LQT-3 to determine what disease-modified channel properties underlie distinct responses to the Na+ channel blocker flecainide. We focused on flecainide block that develops with repetitive channel activity, so-called use-dependent block (UDB). Our results indicate that mutation-induced changes in the voltage-dependence of channel availability (inactivation) may act as determinants of flecainide block. The data further indicate that UDB by flecainide requires channel opening, but is not likely due to open channel block. Rather, flecainide appears to interact with inactivation states that follow depolarization-induced channel opening, and mutation-induced changes in channel inactivation will alter flecainide block independent of the disease to which the mutation is linked. Analysis of flecainide block of mutant channels linked to these rare disorders has provided novel insight into the molecular determinants of drug action.