Role of ryanodine receptor mutations in cardiac pathology: more questions than answers?

The RyR (ryanodine receptor) mediates rapid Ca²⁺ efflux from the ER (endoplasmic reticulum) and is responsible for triggering numerous Ca²⁺-activated physiological processes. The most studied RyR-mediated process is excitation–contraction coupling in striated muscle, where plasma membrane excitation is transmitted to the cell interior and results in Ca²⁺ efflux that triggers myocyte contraction. Recently, single-residue mutations in the cardiac RyR (RyR2) have been identified in families that exhibit CPVT (catecholaminergic polymorphic ventricular tachycardia), a condition in which physical or emotional stress can trigger severe tachyarrhythmias that can lead to sudden cardiac death. The RyR2 mutations in CPVT are clustered in the N- and C-terminal domains, as well as in a central domain. Further, a critical signalling role for dysfunctional RyR2 has also been implicated in the generation of arrhythmias in the common condition of HF (heart failure). We have prepared cardiac RyR2 plasmids with various CPVT mutations to enable expression and analysis of Ca²⁺ release mediated by the wild-type and mutated RyR2. These studies suggest that the mutational locus may be important in the mechanism of Ca²⁺ channel dysfunction. Understanding the causes of aberrant Ca²⁺ release via RyR2 may assist in the development of effective treatments for the ventricular arrhythmias that often leads to sudden death in HF and in CPVT.