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

Michail Nomikos, Angelos Thanassoulas, Konrad Beck, Vyronia Vassilakopoulou, Handan Hu, Brian L. Calver, Maria Theodoridou, Junaid Kashir, Lynda Blayney, Evangelia Livaniou, Pierre Rizkallah, George Nounesis, F. Anthony Lai

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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 Ca 2+-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 Ca 2+ release via aberrant CaMF90L-RyR2 interaction is a potential mechanism that underlies familial IVF.

Original languageBritish English
Pages (from-to)2898-2902
Number of pages5
JournalFEBS Letters
Volume588
Issue number17
DOIs
StatePublished - 25 Aug 2014

Keywords

  • Calcium
  • Calmodulin
  • Idiopathic ventricular fibrillation
  • Ryanodine receptor
  • RyR2 calcium release channel
  • Sudden cardiac death

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