Direct modulation of RyR2 leading to a tricky Ca2+ balance the effects of TRIC-A on cardiac muscle

Abstract

A central point in heart research is to understand the mechanisms behind Ca2+ handling and to find alternatives to correct defective Ca2+ cycling associated with heart failure and arrhythmias. In cardiac myocytes, entry of Ca2+ occurs through L-type Ca2+ channels and mediates the opening of RyR2 (ryanodine receptor 2) channels allowing systolic movement of Ca2+ from the sarcoplasmic reticulum (SR) to the cytosol. In addition, SR Ca2+ release occurs randomly due to RyR2 opening in response to a combination of factors that favor (luminal and cytosolic Ca2+, ATP, posttranslational modifications; gain-of-function mutations or drugs) or preclude it (Mg2+, FKBPs, loss-of-function mutations or drugs). Due to its dependence on luminal SR Ca2+, the concept of SOICR (store overload-induced SR Ca2+ release) has emerged, and the capability of these events to generate delayed afterdepolarizations and arrhythmias is widely accepted. Thus, understanding the mechanisms that regulate SR Ca2+ release and its capacity to promote SOICR is of critical importance.