Distinctive malfunctions of calmodulin mutations associated with heart RyR2-mediated arrhythmic disease

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

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

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.

Original languageBritish English
Pages (from-to)2168-2176
Number of pages9
JournalBBA - General Subjects
Volume1850
Issue number11
DOIs
StatePublished - 2 Nov 2015

Fingerprint

Dive into the research topics of 'Distinctive malfunctions of calmodulin mutations associated with heart RyR2-mediated arrhythmic disease'. Together they form a unique fingerprint.

Cite this