Simulation of L-Type Calcium Currents using Different Experimental Data Sources: from Cell Line to iPS-Derived Cardiomyocyte

Abstract

Drug-induced pro-arrhythmic risk has been one of the main causes for drug candidate failure and has even led to compound withdrawn from the market. A new cardiac safety paradigm that combines in-vitro screening of multiple ion channels and in-silico tools, particularly biophysically-detailed cardiac electrophysiology models, has been encouraged by the FDA, HESI, Cardiac Safety Research Consortium & Safety Pharmacology Society.CaV1.2 channel (conducting the L-type Calcium current (ICaL)) plays an important role in cardiac electrophysiology. Blockade of ICaL can mitigate the pro-arrhythmic risk for multi-channel blockers (e.g. verapamil). For drug development, L-type calcium current data can be obtained from different experimental sources. Cell lines over-expressing the human CaV1.2 channel are normally used for HT compound screening. And recently iPS-derived cardiomyocytes have become an increasingly widespread model in pharmaceutical industry.In this study, the kinetics (steady state activation, inactivation and recovery from inactivation) of CaV1.2 CaL from over-expressed CHO cells and iPS-derived cardiomyocytes were measured using Ca2+ containing or Ba2+ containing solutions (to distinguish between Calcium-dependent and Voltage-dependent inactivations). Several in-silico models were used to emulate the experimental protocols, the simulated ICaL was extracted and compared with experimental data.Comparing simulated traces using data obtained from these two experiment sources, we can learn a lot about the biophysical and biological models and their translational value.