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

FEBS Lett. 2014 Aug 25;588(17):2898-902. doi: 10.1016/j.febslet.2014.07.007. Epub 2014 Jul 15.

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 (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. Ca(2+)-binding studies reveal reduced Ca(2+)-binding affinity and a loss of co-operativity. Moreover, CaM(F90L) displays reduced RyR2 interaction and defective modulation of [(3)H]ryanodine binding. Hence, dysregulation of RyR2-mediated Ca(2+) release via aberrant CaM(F90L)-RyR2 interaction is a potential mechanism that underlies familial IVF.

Keywords: Calcium; Calmodulin; Idiopathic ventricular fibrillation; RyR2 calcium release channel; Ryanodine receptor; Sudden cardiac death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Calcium / metabolism
  • Calmodulin / chemistry
  • Calmodulin / genetics*
  • Calmodulin / metabolism*
  • Death, Sudden, Cardiac*
  • Humans
  • Models, Molecular
  • Mutation*
  • Protein Conformation
  • Ryanodine Receptor Calcium Release Channel / metabolism*
  • Sarcoplasmic Reticulum / metabolism
  • Ventricular Fibrillation / genetics*

Substances

  • Calmodulin
  • Ryanodine Receptor Calcium Release Channel
  • Calcium