Altered RyR2 regulation by the calmodulin F90L mutation associated with idiopathic ventricular fibrillation and early sudden cardiac death
- 15 July 2014
- journal article
- Published by Wiley in FEBS Letters
- Vol. 588 (17) , 2898-2902
Abstract
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 (CaMF90L) was recently identified in a family with idiopathic ventricular fibrillation (IVF) and early onset sudden cardiac death. We report the first biochemical characterization of CaMF90L. F90L confers a deleterious effect on protein stability. Ca2+‐binding studies reveal reduced Ca2+‐binding affinity and a loss of co‐operativity. Moreover, CaMF90L displays reduced RyR2 interaction and defective modulation of [3H]ryanodine binding. Hence, dysregulation of RyR2‐mediated Ca2+ release via aberrant CaMF90L–RyR2 interaction is a potential mechanism that underlies familial IVF.Keywords
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