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

Area of Science:

• Cardiology
• Pharmacology
• Molecular Biology

Background:

• Cardiac repolarization is crucial for heart rhythm, primarily mediated by the I_Kr current through human Ether-à-go-go-Related Gene (hERG) potassium channels.
• Blockage of hERG channels can lead to drug-induced long QT syndrome (LQTS), a dangerous condition causing ventricular arrhythmias.
• Human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) provide a model to study cardiac electrophysiology and drug effects.

Purpose of the Study:

• To investigate the effects of BeKm-1, a scorpion venom peptide, on hiPS-CMs excitability and contractile properties.
• To compare BeKm-1's interaction with hERG channels to reference compounds acting on the intracellular face.
• To evaluate BeKm-1 as a potential molecular platform for designing new hERG modulators.

Main Methods:

• Utilized an automated patch-clamp system to compare BeKm-1 affinity for hERG channels with reference compounds.
• Assessed BeKm-1's impact on hiPS-CMs electrophysiological properties, calcium handling, and beating characteristics.
• Investigated BeKm-1's selective interaction with the extracellular face of hERG channels.

Main Results:

• BeKm-1 delayed cardiomyocyte repolarization, inducing early afterdepolarizations.
• The peptide reduced spontaneous action potentials, calcium transients, and contraction frequencies in hiPS-CMs.
• BeKm-1 recapitulated key phenotypic features of arrhythmic risk observed in drug-induced LQTS.

Conclusions:

• BeKm-1 effectively modulates hiPS-CMs function, mimicking aspects of drug-induced LQTS.
• BeKm-1 serves as a valuable extracellular-acting reference compound for hERG channel research using hiPS-CMs.
• The peptide's modifiable nature makes it an ideal scaffold for developing novel hERG channel modulators.