Structural Integrity of RyR2 Clusters Controls Cardiac Calcium Leak.

Calcium (Ca) leak from the sarcoplasmic reticulum is a key contributor to cardiac arrhythmias, yet the structural mechanisms that regulate spontaneous Ca release from ryanodine receptor type 2 (RyR2) clusters remain poorly understood. To investigate how cluster architecture controls Ca leak, we developed a computational model in which each RyR2 channel is composed of four interacting subunits and embedded within spatially organized clusters. This framework captures both cooperative gating within individual channels and coupling between neighboring channels. Our simulations reveal that the timing of spontaneous Ca sparks is exponentially dependent on the structural integrity of the RyR2 cluster. This exponential sensitivity means that even small disruptions in cluster structural integrity, such as partial fragmentation, can lead to a 100-1000 times increase in spontaneous Ca spark frequency. These findings identify cluster structural integrity as a powerful control mechanism for Ca leak, and represent a promising therapeutic target for restoring Ca homeostasis in cardiac myocytes.