Functional Impact of BeKm-1, a High-Affinity hERG Blocker, on Cardiomyocytes Derived from Human-Induced Pluripotent Stem Cells

高亲和力 hERG 阻滞剂 BeKm-1 对源自人类诱导性多能干细胞的心肌细胞的功能影响

阅读:1
作者:Stephan De Waard, Jérôme Montnach, Barbara Ribeiro, Sébastien Nicolas, Virginie Forest, Flavien Charpentier, Matteo Elia Mangoni, Nathalie Gaborit, Michel Ronjat, Gildas Loussouarn, Patricia Lemarchand, Michel De Waard

Abstract

IKr current, a major component of cardiac repolarization, is mediated by human Ether-à-go-go-Related Gene (hERG, Kv11.1) potassium channels. The blockage of these channels by pharmacological compounds is associated to drug-induced long QT syndrome (LQTS), which is a life-threatening disorder characterized by ventricular arrhythmias and defects in cardiac repolarization that can be illustrated using cardiomyocytes derived from human-induced pluripotent stem cells (hiPS-CMs). This study was meant to assess the modification in hiPS-CMs excitability and contractile properties by BeKm-1, a natural scorpion venom peptide that selectively interacts with the extracellular face of hERG, by opposition to reference compounds that act onto the intracellular face. Using an automated patch-clamp system, we compared the affinity of BeKm-1 for hERG channels with some reference compounds. We fully assessed its effects on the electrophysiological, calcium handling, and beating properties of hiPS-CMs. By delaying cardiomyocyte repolarization, the peptide induces early afterdepolarizations and reduces spontaneous action potentials, calcium transients, and contraction frequencies, therefore recapitulating several of the critical phenotype features associated with arrhythmic risk in drug-induced LQTS. BeKm-1 exemplifies an interesting reference compound in the integrated hiPS-CMs cell model for all drugs that may block the hERG channel from the outer face. Being a peptide that is easily modifiable, it will serve as an ideal molecular platform for the design of new hERG modulators displaying additional functionalities.

特别声明

1、本文转载旨在传播信息,不代表本网站观点,亦不对其内容的真实性承担责任。

2、其他媒体、网站或个人若从本网站转载使用,必须保留本网站注明的“来源”,并自行承担包括版权在内的相关法律责任。

3、如作者不希望本文被转载,或需洽谈转载稿费等事宜,请及时与本网站联系。

4、此外,如需投稿,也可通过邮箱info@biocloudy.com与我们取得联系。