Mechanistic link between CaM-RyR2 interactions and the genesis of cardiac arrhythmia.

In this study, we develop a computational model of the interaction between ryanodine receptor type 2 (RyR2) and calmodulin (CaM) to explore the mechanistic link between CaM-RyR2 interactions and cardiac arrhythmia. Our starting point is a biophysically based computational model of CaM binding to a single RyR2 subunit, which reproduces single-channel RyR2 measurements in lipid bilayers. We then integrate this CaM-RyR2 model into a spatially distributed whole-cell model of Ca cycling, which is used to investigate the relationship between CaM and Ca cycling homeostasis. We show that a reduction in CaM concentration leads to a substantial increase in the rate of spontaneous Ca sparks, and this induces a marked reduction in sarcoplasmic reticulum Ca load during steady-state pacing. Also, we show that a reduction in CaM modifies the RyR2 open probability, which makes the cell more prone to Ca wave propagation. These results indicate that aberrant Ca cycling activity during pacing is determined by the interplay between sarcoplasmic reticulum load reduction and the threshold for Ca wave propagation. Based on these results, we show that when CaM is reduced, Ca waves can occur in a cell and induce action potential perturbations that are arrhythmogenic. Thus, this study outlines a novel, to our knowledge, mechanistic link between CaM-RyR2 binding kinetics and the induction of arrhythmias in the heart.