Size Matters: Ryanodine Receptor Cluster Size Affects Arrhythmogenic Sarcoplasmic Reticulum Calcium Release

Background Ryanodine receptors (RyR) mediate sarcoplasmic reticulum calcium (Ca 2+ ) release and influence myocyte Ca 2+ homeostasis and arrhythmias. In cardiac myocytes, RyRs are found in clusters of various sizes and shapes, and RyR cluster size may critically influence normal and arrhythmogenic Ca 2+ spark and wave formation. However, the actual RyR cluster sizes at specific Ca 2+ spark sites have never been measured in the physiological setting. Methods and Results Here we measured RyR cluster size and Ca 2+ sparks simultaneously to assess how RyR cluster size influences Ca 2+ sparks and sarcoplasmic reticulum Ca 2+ leak. For small RyR cluster sizes (<50), Ca 2+ spark frequency is very low but then increases dramatically at larger cluster sizes. In contrast, Ca 2+ spark amplitude is nearly maximal even at relatively small RyR cluster size (≈10) and changes little at larger cluster size. These properties agreed with computational simulations of RyR gating within clusters. Conclusions Our study explains how this combination of properties may limit arrhythmogenic Ca 2+ sparks and wave propagation (at many junctions) while preserving the efficacy and spatial synchronization of Ca 2+ ‐induced Ca 2+ ‐release during normal excitation‐contraction coupling. However, variations in RyR cluster size among individual junctions and RyR sensitivity could exacerbate heterogeneity of local sarcoplasmic reticulum Ca 2+ release and arrhythmogenesis under pathological conditions.