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

Ryanodine receptors (RyR) mediate sarcoplasmic reticulum calcium (Ca²⁺) release and influence myocyte Ca²⁺ 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 Ca²⁺ spark and wave formation. However, the actual RyR cluster sizes at specific Ca²⁺ spark sites have never been measured in the physiological setting.

Here we measured RyR cluster size and Ca²⁺ sparks simultaneously to assess how RyR cluster size influences Ca²⁺ sparks and sarcoplasmic reticulum Ca²⁺ leak. For small RyR cluster sizes (<50), Ca²⁺ spark frequency is very low but then increases dramatically at larger cluster sizes. In contrast, Ca²⁺ 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.

Our study explains how this combination of properties may limit arrhythmogenic Ca²⁺ sparks and wave propagation (at many junctions) while preserving the efficacy and spatial synchronization of Ca²⁺-induced Ca²⁺-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 Ca²⁺ release and arrhythmogenesis under pathological conditions.