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Updated: May 10, 2026
Dual-Dye Optical Mapping of Hearts from RyR2R2474S Knock-In Mice of Catecholaminergic Polymorphic Ventricular Tachycardia
Published on: December 22, 2023
Abnormal Ca(2+) homeostasis, atrial arrhythmogenesis, and sinus node dysfunction in murine hearts modeling RyR2
Yanmin Zhang1, Gareth D K Matthews, Ming Lei
1Department of Paediatrics, Institute of Shaanxi Province Children's Cardiovascular Diseases, The Shaanxi Provincial People's Hospital of Xi'an Jiaotong University Xi'an, PR of China ; Faculty of Medicine and Human Sciences, Institute of Cardiovascular Sciences, University of Manchester Manchester, UK.
Abstract:
Ryanodine receptor type 2 (RyR2) mutations are implicated in catecholaminergic polymorphic ventricular tachycardia (CPVT) thought to result from altered myocyte Ca(2+) homeostasis reflecting inappropriate "leakiness" of RyR2-Ca(2+) release channels arising from increases in their basal activity, alterations in their phosphorylation, or defective interactions with other molecules or ions. The latter include calstabin, calsequestrin-2, Mg(2+), and extraluminal or intraluminal Ca(2+). Recent clinical studies additionally associate RyR2 abnormalities with atrial arrhythmias including atrial tachycardia (AT), fibrillation (AF), and standstill, and sinus node dysfunction (SND). Some RyR2 mutations associated with CPVT in mouse models also show such arrhythmias that similarly correlate with altered Ca(2+) homeostasis. Some examples show evidence for increased Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of RyR2. A homozygotic RyR2-P2328S variant demonstrates potential arrhythmic substrate resulting from reduced conduction velocity (CV) in addition to delayed afterdepolarizations (DADs) and ectopic action potential (AP) firing. Finally, one model with an increased RyR2 activity in the sino-atrial node (SAN) shows decreased automaticity in the presence of Ca(2+)-dependent decreases in I Ca, L and diastolic sarcoplasmic reticular (SR) Ca(2+) depletion.
Insights
Ryanodine receptor type 2 (RyR2) mutations disrupt calcium (Ca2+) handling, causing cardiac arrhythmias like CPVT. These RyR2 defects are linked to various heart rhythm disorders, impacting myocyte function.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Genetics of Arrhythmias
Background:
- Mutations in Ryanodine receptor type 2 (RyR2) are a known cause of catecholaminergic polymorphic ventricular tachycardia (CPVT).
- RyR2 dysfunction is linked to altered myocyte calcium (Ca2+) homeostasis, characterized by inappropriate Ca2+ release.
- RyR2 interactions with molecules like calstabin, calsequestrin-2, Mg2+, and Ca2+ are crucial for proper channel function.
Purpose of the Study:
- To explore the association between RyR2 abnormalities and a broader spectrum of cardiac arrhythmias beyond CPVT.
- To investigate the mechanisms underlying RyR2-related arrhythmias, including altered Ca2+ homeostasis and phosphorylation.
- To examine the impact of specific RyR2 variants on cardiac electrophysiology and function.
Main Methods:
- Review of recent clinical studies associating RyR2 abnormalities with atrial arrhythmias and sinus node dysfunction.
- Analysis of mouse models exhibiting RyR2 mutations to understand Ca2+ handling and electrophysiological consequences.
- Investigation of molecular mechanisms, including Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation and interactions with other ions and proteins.
Main Results:
- RyR2 abnormalities are linked to atrial tachycardia (AT), atrial fibrillation (AF), atrial standstill, and sinus node dysfunction (SND).
- Specific RyR2 mutations can lead to increased CaMKII phosphorylation, contributing to arrhythmogenesis.
- A RyR2-P2328S variant demonstrated reduced conduction velocity, delayed afterdepolarizations, and ectopic action potential firing.
Conclusions:
- RyR2 mutations are implicated in a wider range of cardiac arrhythmias than previously recognized, including atrial and sinus node dysfunction.
- Altered Ca2+ homeostasis and aberrant RyR2 activity/phosphorylation are key mechanisms driving these arrhythmias.
- Understanding RyR2 pathophysiology is critical for developing therapeutic strategies for diverse cardiac rhythm disorders.
