UC Davis

Background

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.

Methods and results

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.

Conclusions

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.