The cardiac ryanodine receptor-Ca2+ release channel (RyR2) is an essential 
sarcoplasmic reticulum (SR) transmembrane protein that plays a central role in 
excitation-contraction coupling (ECC) in cardiomyocytes. Aberrant spontaneous, 
diastolic Ca2+ leak from the SR due to dysfunctional RyR2 contributes to the 
formation of delayed after-depolarisations, which are thought to underlie the 
fatal arrhythmia that occurs in both heart failure (HF) and in catecholaminergic 
polymorphic ventricular tachycardia (CPVT). CPVT is an inherited disorder 
associated with mutations in either the RyR2 or a SR luminal protein, 
calsequestrin. RyR2 shows normal function at rest in CPVT but the RyR2 
dysfunction is unmasked by physical exercise or emotional stress, suggesting 
abnormal RyR2 activation as an underlying mechanism. Several potential 
mechanisms have been advanced to explain the dysfunctional RyR2 observed in HF 
and CPVT, including enhanced RyR2 phosphorylation status, altered RyR2 
regulation at luminal/cytoplasmic sites and perturbed RyR2 intra/inter-molecular 
interactions. This review considers RyR2 dysfunction in the context of the 
structural and functional modulation of the channel, and potential therapeutic 
strategies to stabilise RyR2 function in cardiac pathology.