Abstract
The cardiac ryanodine receptor (RyR2) is an intracellular Ca
2+
release channel vital for the function of the heart. Physiologically, RyR2 is triggered to release Ca
2+
from the sarcoplasmic reticulum (SR) which enables cardiac contraction; however, spontaneous Ca
2+
leak from RyR2 has been implicated in the pathophysiology of heart failure (HF). RyR2 channels have been well documented to assemble into clusters within the SR membrane, with the organisation of RyR2 clusters recently gaining interest as a mechanism by which the occurrence of pathological Ca
2+
leak is regulated, including in HF. In this review, we explain the terminology relating to key nanoscale RyR2 clustering properties as both single clusters and functionally grouped Ca
2+
release units, with a focus on the advancements in super-resolution imaging approaches which have enabled the detailed study of cluster organisation. Further, we discuss proposed mechanisms for modulating RyR2 channel organisation and the debate regarding the potential impact of cluster organisation on Ca
2+
leak activity. Finally, recent experimental evidence investigating the nanoscale remodelling and functional alterations of RyR2 clusters in HF is discussed with consideration of the clinical implications.