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

doi:10.1016/j.febslet.2014.07.007

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

Biological Sciences

Cardiff University School of Medicine
National Center for Scientific Research demokritos
Cardiff University

Research output: Contribution to journal › Article › peer-review

29 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 (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 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 CaM^F90L-RyR2 interaction is a potential mechanism that underlies familial IVF.

Original language	British English
Pages (from-to)	2898-2902
Number of pages	5
Journal	FEBS Letters
Volume	588
Issue number	17
DOIs	https://doi.org/10.1016/j.febslet.2014.07.007
State	Published - 25 Aug 2014

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

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

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Nomikos, M., Thanassoulas, A., Beck, K., Vassilakopoulou, V., Hu, H., Calver, B. L., Theodoridou, M., Kashir, J., Blayney, L., Livaniou, E., Rizkallah, P., Nounesis, G., & Lai, F. A. (2014). Altered RyR2 regulation by the calmodulin F90L mutation associated with idiopathic ventricular fibrillation and early sudden cardiac death. FEBS Letters, 588(17), 2898-2902. https://doi.org/10.1016/j.febslet.2014.07.007

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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 (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.",

keywords = "Calcium, Calmodulin, Idiopathic ventricular fibrillation, Ryanodine receptor, RyR2 calcium release channel, Sudden cardiac death",

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

note = "Funding Information: VV and MT are research scholars supported by NCSR Demokritos. HH is a research placement scholar supported by the Wales Heart Research Institute. ",

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Nomikos, M, Thanassoulas, A, Beck, K, Vassilakopoulou, V, Hu, H, Calver, BL, Theodoridou, M, Kashir, J, Blayney, L, Livaniou, E, Rizkallah, P, Nounesis, G & Lai, FA 2014, 'Altered RyR2 regulation by the calmodulin F90L mutation associated with idiopathic ventricular fibrillation and early sudden cardiac death', FEBS Letters, vol. 588, no. 17, pp. 2898-2902. https://doi.org/10.1016/j.febslet.2014.07.007

TY - JOUR

T1 - Altered RyR2 regulation by the calmodulin F90L mutation associated with idiopathic ventricular fibrillation and early sudden cardiac death

AU - Nomikos, Michail

AU - Thanassoulas, Angelos

AU - Beck, Konrad

AU - Vassilakopoulou, Vyronia

AU - Hu, Handan

AU - Calver, Brian L.

AU - Theodoridou, Maria

AU - Kashir, Junaid

AU - Blayney, Lynda

AU - Livaniou, Evangelia

AU - Rizkallah, Pierre

AU - Nounesis, George

AU - Lai, F. Anthony

N1 - Funding Information: VV and MT are research scholars supported by NCSR Demokritos. HH is a research placement scholar supported by the Wales Heart Research Institute.

PY - 2014/8/25

Y1 - 2014/8/25

N2 - 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.

AB - 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.

KW - Calcium

KW - Calmodulin

KW - Idiopathic ventricular fibrillation

KW - Ryanodine receptor

KW - RyR2 calcium release channel

KW - Sudden cardiac death

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DO - 10.1016/j.febslet.2014.07.007

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AN - SCOPUS:84906216370

SN - 0014-5793

VL - 588

SP - 2898

EP - 2902

JO - FEBS Letters

JF - FEBS Letters

IS - 17

ER -

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

Abstract

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Keywords

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