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

International Journal of Molecular Sciences

MatteoElia Mangoni¹  Stephan De Waard²  Jérôme Montnach²  Virginie Forest²  Flavien Charpentier²  Michel Ronjat²  Sébastien Nicolas²  Gildas Loussouarn²  Michel De Waard²  Barbara Ribeiro²  Nathalie Gaborit²  Patricia Lemarchand² 

[1] LabEx Ion Channels, Science & Therapeutics, F-06560 Valbonne, France;L’institut du thorax, INSERM, CNRS, UNIV NANTES, F-44007 Nantes, France;

关键词: BeKm-1;    hERG;    LQTS;    hiPS-cardiomyocytes;   

DOI  :  10.3390/ijms21197167

来源: DOAJ

【 摘 要 】

I_Kr current, a major component of cardiac repolarization, is mediated by human Ether-à-go-go-Related Gene (hERG, K_v11.1) 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.

【 授权许可】

Unknown