Ion channel traffic jams: the significance of trafficking deficiency in long QT syndrome.

IF 13 1区 生物学 Q1 CELL BIOLOGY Cell Discovery Pub Date : 2025-01-10 DOI:10.1038/s41421-024-00738-0
Gema Mondéjar-Parreño, Ana I Moreno-Manuel, Juan Manuel Ruiz-Robles, José Jalife
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Abstract

A well-balanced ion channel trafficking machinery is paramount for the normal electromechanical function of the heart. Ion channel variants and many drugs can alter the cardiac action potential and lead to arrhythmias by interfering with mechanisms like ion channel synthesis, trafficking, gating, permeation, and recycling. A case in point is the Long QT syndrome (LQTS), a highly arrhythmogenic disease characterized by an abnormally prolonged QT interval on ECG produced by variants and drugs that interfere with the action potential. Disruption of ion channel trafficking is one of the main sources of LQTS. We review some molecular pathways and mechanisms involved in cardiac ion channel trafficking. We highlight the importance of channelosomes and other macromolecular complexes in helping to maintain normal cardiac electrical function, and the defects that prolong the QT interval as a consequence of variants or the effect of drugs. We examine the concept of "interactome mapping" and illustrate by example the multiple protein-protein interactions an ion channel may undergo throughout its lifetime. We also comment on how mapping the interactomes of the different cardiac ion channels may help advance research into LQTS and other cardiac diseases. Finally, we discuss how using human induced pluripotent stem cell technology to model ion channel trafficking and its defects may help accelerate drug discovery toward preventing life-threatening arrhythmias. Advancements in understanding ion channel trafficking and channelosome complexities are needed to find novel therapeutic targets, predict drug interactions, and enhance the overall management and treatment of LQTS patients.

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离子通道交通阻塞:长QT综合征血运不足的意义。
一个平衡的离子通道运输机制对心脏的正常机电功能至关重要。离子通道变异和许多药物可以通过干扰离子通道合成、运输、门控、渗透和再循环等机制来改变心脏动作电位并导致心律失常。一个典型的例子是长QT综合征(LQTS),这是一种高度致心律失常的疾病,其特征是由干扰动作电位的变异和药物引起的心电图上QT间期异常延长。离子通道贩运的破坏是LQTS的主要来源之一。本文综述了心脏离子通道运输的一些分子途径和机制。我们强调通道体和其他大分子复合物在帮助维持正常心电功能方面的重要性,以及由于变异或药物作用而延长QT间期的缺陷。我们研究了“相互作用组映射”的概念,并举例说明了离子通道在其整个生命周期中可能经历的多种蛋白质-蛋白质相互作用。我们还评论了绘制不同心脏离子通道的相互作用组如何有助于推进LQTS和其他心脏疾病的研究。最后,我们讨论了如何使用人类诱导多能干细胞技术来模拟离子通道运输及其缺陷可能有助于加速药物发现,以预防危及生命的心律失常。在了解离子通道运输和通道体复杂性方面需要取得进展,以发现新的治疗靶点,预测药物相互作用,并加强LQTS患者的整体管理和治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cell Discovery
Cell Discovery Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
24.20
自引率
0.60%
发文量
120
审稿时长
20 weeks
期刊介绍: Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research. Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals. In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.
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