S4153R Is a Gain-of-Function Mutation in the Cardiac Ca2+ Release Channel Ryanodine Receptor Associated With Catecholaminergic Polymorphic Ventricular Tachycardia and Paroxysmal Atrial Fibrillation

2013 ◽  
Vol 29 (8) ◽  
pp. 993-996 ◽  
Author(s):  
Pavel Zhabyeyev ◽  
Florian Hiess ◽  
Ruiwu Wang ◽  
Yingjie Liu ◽  
S.R. Wayne Chen ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Ventricular Tachycardia ◽  
Ryanodine Receptor ◽  
Paroxysmal Atrial Fibrillation ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Polymorphic Ventricular Tachycardia ◽  
Gain Of Function ◽  
Release Channel

scholarly journals Multiphoton Imaging of Ca2+ Instability in Acute Myocardial Slices from a RyR2R2474S Murine Model of Catecholaminergic Polymorphic Ventricular Tachycardia

2021 ◽  
Vol 10 (13) ◽  
pp. 2821
Author(s):  
Giulia Borile ◽  
Tania Zaglia ◽  
Stephan E. Lehnart ◽  
Marco Mongillo
Keyword(s):  
Ventricular Tachycardia ◽  
Single Cells ◽  
Tissue Level ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Polymorphic Ventricular Tachycardia ◽  
Adrenergic Stimulation ◽  
Release Channel ◽  
Multiphoton Imaging ◽  
Delayed Afterdepolarizations ◽  
Multiple Cells

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a familial stress-induced arrhythmia syndrome, mostly caused by mutations in Ryanodine receptor 2 (RyR2), the sarcoplasmic reticulum (SR) Ca2+ release channel in cardiomyocytes. Pathogenetic mutations lead to gain of function in the channel, causing arrhythmias by promoting diastolic spontaneous Ca2+ release (SCR) from the SR and delayed afterdepolarizations. While the study of Ca2+ dynamics in single cells from murine CPVT models has increased our understanding of the disease pathogenesis, questions remain on the mechanisms triggering the lethal arrhythmias at tissue level. Here, we combined subcellular analysis of Ca2+ signals in isolated cardiomyocytes and in acute thick ventricular slices of RyR2R2474S knock-in mice, electrically paced at different rates (1–5 Hz), to identify arrhythmogenic Ca2+ dynamics, from the sub- to the multicellular perspective. In both models, RyR2R2474S cardiomyocytes had increased propensity to develop SCR upon adrenergic stimulation, which manifested, in the slices, with Ca2+ alternans and synchronous Ca2+ release events in neighboring cardiomyocytes. Analysis of Ca2+ dynamics in multiple cells in the tissue suggests that SCRs beget SCRs in contiguous cells, overcoming the protective electrotonic myocardial coupling, and potentially generating arrhythmia triggering foci. We suggest that intercellular interactions may underscore arrhythmic propensity in CPVT hearts with ‘leaky’ RyR2.

scholarly journals The arrhythmogenic N53I variant subtly changes the structure and dynamics in the calmodulin N-terminal domain, altering its interaction with the cardiac ryanodine receptor

2020 ◽  
Vol 295 (22) ◽  
pp. 7620-7634
Author(s):  
Christian Holt ◽  
Louise Hamborg ◽  
Kelvin Lau ◽  
Malene Brohus ◽  
Anders Bundgaard Sørensen ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Ryanodine Receptor ◽  
Hydrophobic Surface ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Polymorphic Ventricular Tachycardia ◽  
Open Probability ◽  
Calmodulin Binding ◽  
Terminal Domain ◽  
Genes Encoding ◽  
Cardiac Ryanodine Receptor

Mutations in the genes encoding the highly conserved Ca2+-sensing protein calmodulin (CaM) cause severe cardiac arrhythmias, including catecholaminergic polymorphic ventricular tachycardia or long QT syndrome and sudden cardiac death. Most of the identified arrhythmogenic mutations reside in the C-terminal domain of CaM and mostly affect Ca2+-coordinating residues. One exception is the catecholaminergic polymorphic ventricular tachycardia–causing N53I substitution, which resides in the N-terminal domain (N-domain). It does not affect Ca2+ coordination and has only a minor impact on binding affinity toward Ca2+ and on other biophysical properties. Nevertheless, the N53I substitution dramatically affects CaM's ability to reduce the open probability of the cardiac ryanodine receptor (RyR2) while having no effect on the regulation of the plasmalemmal voltage-gated Ca2+ channel, Cav1.2. To gain more insight into the molecular disease mechanism of this mutant, we used NMR to investigate the structures and dynamics of both apo- and Ca2+-bound CaM-N53I in solution. We also solved the crystal structures of WT and N53I CaM in complex with the primary calmodulin-binding domain (CaMBD2) from RyR2 at 1.84–2.13 Å resolutions. We found that all structures of the arrhythmogenic CaM-N53I variant are highly similar to those of WT CaM. However, we noted that the N53I substitution exposes an additional hydrophobic surface and that the intramolecular dynamics of the protein are significantly altered such that they destabilize the CaM N-domain. We conclude that the N53I-induced changes alter the interaction of the CaM N-domain with RyR2 and thereby likely cause the arrhythmogenic phenotype of this mutation.

scholarly journals Tetrodotoxin‐Sensitive Neuronal‐Type Na + Channels: A Novel and Druggable Target for Prevention of Atrial Fibrillation

2020 ◽  
Vol 9 (11) ◽  
Author(s):  
Mark A. Munger ◽  
Yusuf Olğar ◽  
Megan L. Koleske ◽  
Heather L. Struckman ◽  
Jessica Mandrioli ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Ventricular Tachycardia ◽  
Medical Center ◽  
Close Association ◽  
Academic Medical Center ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Polymorphic Ventricular Tachycardia ◽  
Atrial Arrhythmias ◽  
Neuronal Type

Background Atrial fibrillation (AF) is a comorbidity associated with heart failure and catecholaminergic polymorphic ventricular tachycardia. Despite the Ca 2+ ‐dependent nature of both of these pathologies, AF often responds to Na + channel blockers. We investigated how targeting interdependent Na + /Ca 2+ dysregulation might prevent focal activity and control AF. Methods and Results We studied AF in 2 models of Ca 2+ ‐dependent disorders, a murine model of catecholaminergic polymorphic ventricular tachycardia and a canine model of chronic tachypacing‐induced heart failure. Imaging studies revealed close association of neuronal‐type Na + channels (nNa v ) with ryanodine receptors and Na + /Ca 2+ exchanger. Catecholamine stimulation induced cellular and in vivo atrial arrhythmias in wild‐type mice only during pharmacological augmentation of nNa v activity. In contrast, catecholamine stimulation alone was sufficient to elicit atrial arrhythmias in catecholaminergic polymorphic ventricular tachycardia mice and failing canine atria. Importantly, these were abolished by acute nNa v inhibition (tetrodotoxin or riluzole) implicating Na + /Ca 2+ dysregulation in AF. These findings were then tested in 2 nonrandomized retrospective cohorts: an amyotrophic lateral sclerosis clinic and an academic medical center. Riluzole‐treated patients adjusted for baseline characteristics evidenced significantly lower incidence of arrhythmias including new‐onset AF, supporting the preclinical results. Conclusions These data suggest that nNa V s mediate Na + ‐Ca 2+ crosstalk within nanodomains containing Ca 2+ release machinery and, thereby, contribute to AF triggers. Disruption of this mechanism by nNa v inhibition can effectively prevent AF arising from diverse causes.

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