Altered RyR2 regulation by the calmodulin F90L mutation associated with idiopathic ventricular fibrillation and early sudden cardiac death

Calmodulin (CaM) association with the cardiac muscle ryanodine receptor (RyR2) regulates excitation–contraction coupling. Defective CaM–RyR2 interaction is associated with heart failure. A novel CaM mutation (CaM^F90L) was recently identified in a family with idiopathic ventricular fibrillation (IVF) and early onset sudden cardiac death. We report the first biochemical characterization of CaM^F90L. F90L confers a deleterious effect on protein stability. Ca²⁺-binding studies reveal reduced Ca²⁺-binding affinity and a loss of co-operativity. Moreover, CaM^F90L displays reduced RyR2 interaction and defective modulation of [³H]ryanodine binding. Hence, dysregulation of RyR2-mediated Ca²⁺ release via aberrant CaM^F90L–RyR2 interaction is a potential mechanism that underlies familial IVF.