Referenced in: none

Automatically associated channels: Kv7.1

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

Authors: 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

Journal, date & volume: Biochim. Biophys. Acta, 2015 Nov , 1850, 2168-76

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/26164367

Abstract
Calmodulin (CaM) is a cytoplasmic calcium sensor that interacts with the cardiac ryanodine receptor (RyR2), a large Ca(2+) channel complex that mediates Ca(2+) 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. Ca(2+)-binding studies indicate that the CPVT-associated CaM mutations, N54I & N98S, exhibit the same or a 3-fold reduced Ca(2+)-binding affinity, respectively, versus wild-type CaM, whereas the LQTS-associated CaM mutants, D96V, D130G & F142L, display more profoundly reduced Ca(2+)-binding affinity. In contrast, all five CaM mutations confer a disparate RyR2 interaction and modulation of [(3)H]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 Ca(2+)-binding as well as defective interaction with RyR2.