title: Altered RyR2 regulation by the calmodulin F90L mutation associated with idiopathic ventricular fibrillation and early sudden cardiac death.
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.
authors.affiliation: Wales Heart Research Institute, Cardiff University School of Medicine, Institute of Molecular and Experimental Medicine, Cardiff CF14 4XN, UK. Electronic address: mixosn@yahoo.com.
authors.forename: Michail
authors.initials: M
authors.lastname: Nomikos
authors.affiliation: National Center for Scientific Research "Demokritos", 15310 Aghia Paraskevi, Greece.
authors.forename: Angelos
authors.initials: A
authors.lastname: Thanassoulas
authors.affiliation: School of Dentistry, Cardiff University, Cardiff CF14 4XY, UK.
authors.forename: Konrad
authors.initials: K
authors.lastname: Beck
authors.affiliation: Wales Heart Research Institute, Cardiff University School of Medicine, Institute of Molecular and Experimental Medicine, Cardiff CF14 4XN, UK; National Center for Scientific Research "Demokritos", 15310 Aghia Paraskevi, Greece.
authors.forename: Vyronia
authors.initials: V
authors.lastname: Vassilakopoulou
authors.affiliation: Wales Heart Research Institute, Cardiff University School of Medicine, Institute of Molecular and Experimental Medicine, Cardiff CF14 4XN, UK.
authors.forename: Handan
authors.initials: H
authors.lastname: Hu
authors.affiliation: Wales Heart Research Institute, Cardiff University School of Medicine, Institute of Molecular and Experimental Medicine, Cardiff CF14 4XN, UK.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Calver
authors.affiliation: Wales Heart Research Institute, Cardiff University School of Medicine, Institute of Molecular and Experimental Medicine, Cardiff CF14 4XN, UK; National Center for Scientific Research "Demokritos", 15310 Aghia Paraskevi, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Theodoridou
authors.affiliation: Wales Heart Research Institute, Cardiff University School of Medicine, Institute of Molecular and Experimental Medicine, Cardiff CF14 4XN, UK.
authors.forename: Junaid
authors.initials: J
authors.lastname: Kashir
authors.affiliation: Wales Heart Research Institute, Cardiff University School of Medicine, Institute of Molecular and Experimental Medicine, Cardiff CF14 4XN, UK.
authors.forename: Lynda
authors.initials: L
authors.lastname: Blayney
authors.affiliation: National Center for Scientific Research "Demokritos", 15310 Aghia Paraskevi, Greece.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Livaniou
authors.affiliation: Wales Heart Research Institute, Cardiff University School of Medicine, Institute of Molecular and Experimental Medicine, Cardiff CF14 4XN, UK.
authors.forename: Pierre
authors.initials: P
authors.lastname: Rizkallah
authors.affiliation: National Center for Scientific Research "Demokritos", 15310 Aghia Paraskevi, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Nounesis
authors.affiliation: Wales Heart Research Institute, Cardiff University School of Medicine, Institute of Molecular and Experimental Medicine, Cardiff CF14 4XN, UK.
authors.forename: F Anthony
authors.initials: FA
authors.lastname: Lai
mesh_terms: D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D016757:Death, Sudden, Cardiac; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D014693:Ventricular Fibrillation / Q000235:genetics*
chemical_list: D002147:Calmodulin; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium
keywords: Calcium; Calmodulin; Idiopathic ventricular fibrillation; RyR2 calcium release channel; Ryanodine receptor; Sudden cardiac death