Mutations in cardiac sodium channels: clinical implications.
Mutations in cardiac sodium channels: clinical implications.
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DOI：
10.2165/00129785-200303030-00003
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发表时间：
2003-01-01
期刊：
影响因子：
--
通讯作者：
Kass, Robert
中科院分区：
文献类型：
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作者：
Liu, Huajun;Clancy, Colleen;Kass, Robert
电压门控钠通道（VGSCs）是大多数可兴奋细胞中负责快速动作电位上升的关键跨膜蛋白。最近发现的VGSCs突变是特发性临床疾病的基础，强调了这些通道在骨骼肌、神经系统和心肌等组织中的重要性。编码心脏钠通道异构体（SCN5A）的基因突变与至少三种异常表型有关：长QT综合征（LQT-3）的变体3；Brugada综合征；孤立性心脏传导疾病（ICCD）。SCN5A突变表现为一种或多种临床表型——这些疾病之间的精确区别越来越微妙。LQT-3的临床治疗和局麻药氟氯胺对BrS的诊断是有希望的。与LQT-3 （D1790G）和BrS （Y1795H）相关的通道对氟氯胺的敏感性均高于野生型（WT）通道，而对利多卡因的敏感性不变。对不同药物敏感性的一种合理解释是，与WT相比，突变通道可能通过改变动作电位期间的蛋白质变构变化而允许更多地进入受体位点。局部麻醉阻滞的高亲和力结合位点已经在通道的孔区被确定。在封闭状态下，该区域无法进入水，因此需要打开通道以使带电药物（弗莱卡因和美西汀）进入和阻断。破坏失活生物物理的通道突变通过改变结合位点在动作电位期间可接近的时间而导致药物结合增加。中性药物（利多卡因）不依赖于通道打开来进入结合位点，对改变通道失活特性的突变不敏感。有趣的是，另一个LQT-3突变体（Y1795C）对氟氯胺的敏感性没有变化，这表明尽管SCN5A突变的药物作用跨越了疾病界限，但氟氯胺的临床管理将以突变特异性的方式对患者有益。
Voltage-gated sodium channels (VGSCs) are critical transmembrane proteins responsible for the rapid action potential upstroke in most excitable cells. Recently discovered mutations in VGSCs, which underlie idiopathic clinical disease, have emphasized the importance of these channels in tissues such as skeletal muscle, nervous system, and myocardium. Mutations in the gene encoding the cardiac sodium channel isoform (SCN5A) have been linked to at least three abnormal phenotypes: variant 3 of the Long QT syndrome (LQT-3); Brugada's syndrome (BrS); and isolated cardiac conduction disease (ICCD). Mutations in SCN5A manifest as one or more of these clinical phenotypes - the precise distinction between these diseases is increasingly subtle. Clinical management of LQT-3 and diagnosis of BrS with the local anesthetic flecainide has proven promising. Channels associated with LQT-3 (D1790G) and BrS (Y1795H) both show more sensitivity to flecainide than wild-type (WT) channels, while lidocaine sensitivity is unchanged. One plausible explanation for differential drug sensitivity is that mutant channels may allow more access to a receptor site compared with WT through altered protein allosteric changes during an action potential. The high affinity binding site for local anesthetic block has been identified in the pore region of the channel. This region is not water accessible during the closed state, thus requiring channel opening for charged drug (flecainide and mexiletine) access and block. Channel mutations which disrupt inactivation biophysics lead to increased drug binding by altering the time the binding site is accessible during an action potential. Neutral drugs (lidocaine) which are not dependent on channel opening for binding site access will not be sensitive to mutations that alter channel inactivation properties. Interestingly another LQT-3 mutant (Y1795C) shows no change in flecainide sensitivity, suggesting that although drug effects of SCN5A mutations cross disease boundaries, clinical management with flecainide will be beneficial to patients in a mutation-specific manner.