'Ryanopathy': causes and manifestations of RyR2 dysfunction in heart failure

The cardiac ryanodine receptor (RyR2), a Ca-2 release channel on the membrane of the sarcoplasmic reticulum (SR), plays a key role in determining the strength of the heartbeat by supplying Ca-2 required for contractile activation. Abnormal RyR2 function is recognized as an important part of the pathophysiology of heart failure (HF). While in the normal heart, the balance between the cytosolic and intra-SR Ca-2 regulation of RyR2 function maintains the contractionrelaxation cycle, in HF, this behaviour is compromised by excessive post-translational modifications of the RyR2. Such modification of the Ca-2 release channel impairs the ability of the RyR2 to properly deactivate leading to a spectrum of Ca-2-dependent pathologies that include cardiac systolic and diastolic dysfunction, arrhythmias, and structural remodelling. In this article, we present an overview of recent advances in our understanding of the underlying causes and pathological consequences of abnormal RyR2 function in the failing heart. We also discuss the implications of these findings for HF therapy.