TY - JOUR
T1 - Distinctive malfunctions of calmodulin mutations associated with heart RyR2-mediated arrhythmic disease
AU - Vassilakopoulou, Vyronia
AU - Calver, Brian L.
AU - Thanassoulas, Angelos
AU - Beck, Konrad
AU - Hu, Handan
AU - Buntwal, Luke
AU - Smith, Adrian
AU - Theodoridou, Maria
AU - Kashir, Junaid
AU - Blayney, Lynda
AU - Livaniou, Evangelia
AU - Nounesis, George
AU - Lai, F. Anthony
AU - Nomikos, Michail
N1 - Funding Information:
VV and AS are research scholars supported by NCSR Demokritos and the Sir Geraint Evans Wales Heart Research Institute, respectively. JK and MN are supported by a Health Fellowship award (National Institute for Social Care and Health Research) and by a Marie Curie Intra-European Research Fellowship, respectively.
Publisher Copyright:
© 2015 Elsevier B.V. All rights reserved.
PY - 2015/11/2
Y1 - 2015/11/2
N2 - Calmodulin (CaM) is a cytoplasmic calcium sensor that interacts with the cardiac ryanodine receptor (RyR2), a large Ca2 + channel complex that mediates Ca2 + efflux from the sarcoplasmic reticulum (SR) to activate cardiac muscle contraction. Direct CaM association with RyR2 is an important physiological regulator of cardiac muscle excitation-contraction coupling and defective CaM-RyR2 protein interaction has been reported in cases of heart failure. Recent genetic studies have identified CaM missense mutations in patients with a history of severe cardiac arrhythmogenic disorders that present divergent clinical features, including catecholaminergic polymorphic ventricular tachycardia (CPVT), long QT syndrome (LQTS) and idiopathic ventricular fibrillation (IVF). Herein, we describe how two CPVT- (N54I & N98S) and three LQTS-associated (D96V, D130G & F142L) CaM mutations result in alteration of their biochemical and biophysical properties. Ca2 +-binding studies indicate that the CPVT-associated CaM mutations, N54I & N98S, exhibit the same or a 3-fold reduced Ca2 +-binding affinity, respectively, versus wild-type CaM, whereas the LQTS-associated CaM mutants, D96V, D130G & F142L, display more profoundly reduced Ca2 +-binding affinity. In contrast, all five CaM mutations confer a disparate RyR2 interaction and modulation of [3H]ryanodine binding to RyR2, regardless of CPVT or LQTS association. Our findings suggest that the clinical presentation of CPVT or LQTS associated with these five CaM mutations may involve both altered intrinsic Ca2 +-binding as well as defective interaction with RyR2.
AB - Calmodulin (CaM) is a cytoplasmic calcium sensor that interacts with the cardiac ryanodine receptor (RyR2), a large Ca2 + channel complex that mediates Ca2 + efflux from the sarcoplasmic reticulum (SR) to activate cardiac muscle contraction. Direct CaM association with RyR2 is an important physiological regulator of cardiac muscle excitation-contraction coupling and defective CaM-RyR2 protein interaction has been reported in cases of heart failure. Recent genetic studies have identified CaM missense mutations in patients with a history of severe cardiac arrhythmogenic disorders that present divergent clinical features, including catecholaminergic polymorphic ventricular tachycardia (CPVT), long QT syndrome (LQTS) and idiopathic ventricular fibrillation (IVF). Herein, we describe how two CPVT- (N54I & N98S) and three LQTS-associated (D96V, D130G & F142L) CaM mutations result in alteration of their biochemical and biophysical properties. Ca2 +-binding studies indicate that the CPVT-associated CaM mutations, N54I & N98S, exhibit the same or a 3-fold reduced Ca2 +-binding affinity, respectively, versus wild-type CaM, whereas the LQTS-associated CaM mutants, D96V, D130G & F142L, display more profoundly reduced Ca2 +-binding affinity. In contrast, all five CaM mutations confer a disparate RyR2 interaction and modulation of [3H]ryanodine binding to RyR2, regardless of CPVT or LQTS association. Our findings suggest that the clinical presentation of CPVT or LQTS associated with these five CaM mutations may involve both altered intrinsic Ca2 +-binding as well as defective interaction with RyR2.
UR - http://www.scopus.com/inward/record.url?scp=84940562260&partnerID=8YFLogxK
U2 - 10.1016/j.bbagen.2015.07.001
DO - 10.1016/j.bbagen.2015.07.001
M3 - Article
C2 - 26164367
AN - SCOPUS:84940562260
SN - 0304-4165
VL - 1850
SP - 2168
EP - 2176
JO - BBA - General Subjects
JF - BBA - General Subjects
IS - 11
ER -