Dysregulated sarcoplasmic reticulum calcium release: Potential pharmacological target in cardiac disease

In the heart, Ca2+ released from the intracellular Ca2+ storage site, the sarcoplasmic reticulum (SR), is the principal determinant of cardiac contractility. SR Ca2+ release is controlled by dedicated molecular machinery, composed of the cardiac ryanodine receptor (RyR2) and a number of accessory proteins, including FKBP12.6, calsequestrin (CASQ2), triadin (TRD) and junctin (JN). Acquired and genetic defects in the components of the release channel complex result in a spectrum of abnormal Ca2+ release phenotypes ranging from arrhythmogenic spontaneous Ca2+ releases and Ca2+ alternans to the uniformly diminished systolic Ca2+ release characteristic of heart failure. In this article, we will present an overview of the structure and molecular components of the SR and Ca2+ release machinery and its modulation by different intracellular factors, such as Ca2+ levels inside the SR as well as phosphorylation and redox modification of RyR2s. We will also discuss the relationships between abnormal SR Ca2+ release and various cardiac disease phenotypes, including, arrhythmias and heart failure, and consider SR Ca2+ release as a potential therapeutic target.