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

Vassilakopoulou, Vyronia, Calver, Brian, Thanassoulas, Angelos, Beck, Konrad ORCID: https://orcid.org/0000-0001-5098-9484, Hu, Handan, Buntwal, Luke, Smith, Adrian, Theodoridou, Maria, Kashir, Junaid, Blayney, Lynda, Livaniou, Evangelia, Nounesis, George, Lai, Francis ORCID: https://orcid.org/0000-0003-2852-8547 and Nomikos, Michail 2015. Distinctive malfunctions of calmodulin mutations associated with heart RyR2-mediated arrhythmic disease. Biochimica et Biophysica Acta (BBA) - General Subjects 1850 (11) , pp. 2168-2176. 10.1016/j.bbagen.2015.07.001

Full text not available from this repository.

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences Dentistry Medicine
Subjects:	R Medicine > R Medicine (General)
Publisher:	Elsevier
ISSN:	0304-4165
Funders:	NISCHR
Date of Acceptance:	2 July 2015
Last Modified:	05 Jan 2024 08:15
URI:	https://orca.cardiff.ac.uk/id/eprint/80368

Citation Data

Cited 22 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item