Aims: 

The ryanodine receptor-calcium release channel (RyR) is an integral membrane protein responsible for the calcium efflux that triggers numerous calcium-activated physiological processes, including muscle contraction, neurotransmitter release and hormone secretion. Recently, approximately 70 single residue mutations in the cardiac RyR2 were identified in families that exhibit catecholaminergic polymorphic ventricular tachycardia (CPVT), a condition in which physical or emotional stress can trigger severe tachyarrhythmias that can lead to sudden cardiac death. Our laboratory aims to characterise the dysfunction underlying the cardiac pathology due to these mutant RyR2s.

Methods: 

The RyR2 mutations in CPVT are clustered in the N- and C-terminal domains, as well as in a central domain. We have cloned the full-length cDNA encoding human RyR2 and generated expression plasmids with various CPVT mutations across the RyR2 sequence to enable the heterologous expression and analysis of calcium release mediated by the wild type and mutated RyR2.

Results: 

Our studies employing confocal microscopy, calcium fluorometry, FRET and biochemical analysis suggest that the mutational locus may be a significant factor in the mechanism underlying RyR2-mediated calcium channel dysfunction.

Conclusion: 

Further understanding the causes of aberrant calcium release via RyR2 should assist in the development of effective treatments for the ventricular arrhythmias that often leads to sudden death in both heart failure and in CPVT (Thomas et al. Biochem Soc Trans 34, 913-918, 2006; George et al. J Mol Cell Cardiol 42, 34-50, 2007).