Fifty Shades of Calpain: Couplon Breakdown in Catecholaminergic Polymorphic Ventricular Tachycardia and Beyond
Year: 2026
Type: editorial
Abstract: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic syndrome that primarily affects children and young adults and is characterized by potentially fatal ventricular arrhythmias triggered by physical or emotional stress in a structurally normal heart. 1 CPVT is caused by aberrant sarcoplasmic reticulum (SR) calcium (Ca) release due to genetic variants in ryanodine receptor 2 (RyR2), cardiac calsequestrin (Casq2) and associated proteins, which are the key components of the cardiomyocyte junctional SR complex (couplon) responsible for coordinating SR Ca release. 2 While RyR2 mutations account for most cases, 3 Casq2 mutations are associated with a less common but often more severe form of CPVT. 4 Notably, Casq2-mutant mouse models exhibit reduced levels of Casq2 and its protein partners triadin and junctin, along with abnormal Ca release and triggered electrical activity.5 However, the mechanisms driving this coordinated loss of couplon proteins and its role in CPVT pathogenesis remain incompletely understood.In this issue, Ramos-Hernández et al. 6 provide a new perspective on how disruption of the couplon proteins contributes to Casq2-associated CPVT.Using the homozygous Casq2 R33Q/R33Q mouse model that recapitulates the human CPVT phenotype, the authors address a longstanding observation: mutant hearts exhibit markedly reduced Casq2, triadin (TRDN), and junctin (JCTN) protein despite preserved RNA transcript expression.7 Through proteomic profiling and complementary pharmacological studies, they demonstrate that these proteins are not lost through a single pathway.Mutant Casq2 is targeted by endoplasmic reticulum (ER)-associated degradation, the ubiquitin-proteasome system, and autophagy, whereas TRDN emerges as a direct substrate of the Ca-activated protease calpain.6 Importantly, TRDN degradation occurs more rapidly than Casq2 loss, and restoring TRDN by modified RNA in cardiomyocytes or AAV-mediated expression in vivo increases
Source: Circulation Research
Authors: Tri Q. Do, Björn C. Knollmann
Institution: Vanderbilt University Medical Center
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7223250633