The ryanodine receptor-calcium release channel (RyR) is an integral membrane protein that mediates rapid calcium efflux from the endoplasmic reticulum. RyRs play a direct role in the calcium signalling that is responsible for triggering numerous calcium-activated physiological processes, including contraction, neurotransmitter release and hormone secretion. The most characterised RyR-mediated process is excitation-contraction coupling in striated muscle, where electrical excitation of the plasma membrane is transmitted to the cell interior and results in a massive calcium efflux that triggers myocyte contraction (1,2,3). The RyR is a homotetramer of 560,000 Dalton subunits, forming a ~2.3 megaDalton complex that associates with a multitude of accessory proteins including calmodulin, FK506 binding protein (FKBP12), calsequestrin, snapin, triadin and sorcin (1). The predicted transmembrane domain is located in the C-terminal one fifth of the molecule with the remaining ~80% thought to project into the cytoplasm. Several phosphorylation sites are located on the cytoplasmic portion that can regulate accessory protein interactions and channel function. The RyR complex comprises a ion permeation pathway of high unitary conductance that is weakly selective for divalent versus monovalent cations. Recently, approximately 70 single residue mutations in the cardiac RyR2 have been 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 (1,2,3). 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 heart failure. We have cloned the full-length cDNA encoding human cardiac RyR (RyR2) and generated RyR2 plasmids with various CPVT mutations to enable the heterologous expression and analysis of calcium release mediated by the wild type and mutated RyR2. These studies suggest that the mutational locus may be a significant factor in the mechanism underlying RyR2-mediated calcium channel dysfunction (1,2,3,4). 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.