Proteins Associated with the Cardiac Ryanodine Receptor Alter the Threshold for Store Overload-Induced Calcium Release

Abstract

The cardiac ryanodine receptor (RyR2) forms the core of a large macromolecular complex with other proteins termed “RyR2 associated proteins”. In heart disease, altered expression of these RyR2 associated proteins can lead to inappropriate opening of RyR2 and trigger arrhythmia. However, the mechanism by which changes in the expression of these proteins alters the activity of RyR2 remains unknown. Using HEK293 cells expressing RyR2 with or without co-expression of 12.6 kDa FK506-binding protein (FKBP12.6) or triadin, we examined whether these RyR2 associated proteins could modify the activity of RyR2 by altering its susceptibility to Store Overload-Induced Calcium Release (SOICR). Our data show that FKBP12.6 does not alter initiation of SOICR, but does reduce the amount of Ca2+ released during each event. Whereas triadin decreases the propensity for SOICR, by increasing the level of store Ca2+ required to initiate SOICR, it does not alter the amount of Ca2+ released per event. Collectively, these data suggest that changes in the RyR2 protein complex lead to arrhythmia by altering the susceptibly or magnitude of SOICR.