Interplay Between Ryanodine Receptor Arrangement and Function: Implications for (Patho)physiological Control of Calcium Release

Calcium release through the cardiac RyR2 (type-2 ryanodine receptor) is essential for cardiac contraction. RyR2 dysfunction is associated with a spectrum of cardiac pathologies, most notably arrhythmias. While excessive RyR2 activity was historically seen as the driver of arrhythmia, it is now clear that inadequate calcium release is equally detrimental. This homeostatic balance of activity requires precise tuning, which is provided by a swathe of regulating factors spanning posttranslational modifications, protein-protein interactions, and the more recently identified positioning of individual RyR2 channels within the cell. This review summarizes how too much, or too little, calcium release can lead to arrhythmia and explores how the multitude of regulating factors work synergistically to set and modify RyR2 physiologically and become impaired in disease. Finally, we examine how RyR2-targeted pharmacological approaches can therapeutically rebalance calcium handling and inhibit arrhythmia.