Cellular and Molecular Arrhythmia Research Program, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53792, USA.
J Cardiovasc Pharmacol. 2010 Aug;56(2):113-22. doi: 10.1097/FJC.0b013e3181dab014.
Inherited arrhythmia syndromes comprise an increasingly complex group of diseases involving mutations in multiple genes encoding ion channels, ion channel accessory subunits and channel interacting proteins, and various regulatory elements. These mutations serve to disrupt normal electrophysiology in the heart, leading to increased arrhythmogenic risk and death. These diseases have added impact as they often affect young people, sometimes without warning. Although originally thought to alter ion channel function, it is now increasingly recognized that mutations may alter ion channel protein and messenger RNA processing, to reduce the number of channels reaching the surface membrane. For many of these mutations, it is also known that several interventions may restore protein processing of mutant channels to increase their surface membrane expression toward normal. In this article, we reviewed inherited arrhythmia syndromes, focusing on long QT syndrome type 2, and discuss the complex biology of ion channel trafficking and pharmacological rescue of disease-causing mutant channels. Pharmacological rescue of misprocessed mutant channel proteins, or their transcripts providing appropriate small molecule drugs can be developed, has the potential for novel clinical therapies in some patients with inherited arrhythmia syndromes.
遗传性心律失常综合征包括一组日益复杂的疾病，涉及编码离子通道、离子通道辅助亚基和通道相互作用蛋白以及各种调节元件的多个基因突变。这些突变会破坏心脏的正常电生理，导致心律失常风险增加和死亡。这些疾病的影响更大，因为它们经常在没有预警的情况下影响年轻人。尽管最初认为这些突变会改变离子通道的功能，但现在越来越多的人认识到，突变可能会改变离子通道蛋白和信使 RNA 的加工，从而减少到达质膜的通道数量。对于许多这些突变，也已知几种干预措施可以恢复突变通道的蛋白加工，以增加其质膜表达至正常水平。在本文中，我们综述了遗传性心律失常综合征，重点介绍了 2 型长 QT 综合征，并讨论了离子通道运输的复杂生物学和致病突变通道的药理学挽救。对于某些遗传性心律失常综合征患者，对错误加工的突变通道蛋白或其提供适当小分子药物的转录本进行药理学挽救，有可能开发出新型临床治疗方法。
