The emerging role of calsequestrin 2: from calcium sensor and modulator to arrhythmia driver

Journal article : Review

Calsequestrin 2 (CASQ2) has emerged as a central sensor and modulator of calcium (Ca2+) dynamics in sarcoplasmic reticulum (SR), influencing both health and disease. This review explores the molecular architecture and multifunctional roles of CASQ2, beginning with its domain organization and Ca2+-binding properties and detecting how its folding and supramolecular assembly modulate Ca2+ storage and release within cardiac muscle. Post-translational modifications, genetic regulatory mechanisms and CASQ2’s multipartner interactome; including Ryanodine receptor 2 (RyR2), triadin and junctin are also discussed to highlight potential models in which complex stoichiometry and luminal Ca2+ dictate channel refractoriness and excitation-contraction coupling. Disruption of CASQ2 function is increasingly recognized as a driver of certain types of arrhythmias, notably catecholaminergic polymorphic ventricular tachycardia (CPVT) and heightened risk of sudden cardiac death. This review appraises contemporary therapies that focus on pharmacological and device-based interventions and surveys next-generation strategies that aim to directly stabilize CASQ2 or target its gene expression. Despite therapeutic advances, the challenges remain; and a translational agenda aligning mechanism with therapy is proposed. By integrating recent structural, functional, regulatory and pathological insights, this review provides a conceptual framework for the pivotal role of CASQ2 in arrhythmogenesis and positions CASQ2 biology at the center of precision cardiology.

Authors: Rajha, HE; Abuajameia, BH; Barhoma, AM; Hashem, IE; Islam, Z

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer
• Journal: Journal of Physiology and Biochemistry
• Volume: 82
• Issue: 1
• Article number: 6
• Publication date: 2026-02-02
• Acceptance date: 2025-12-22
• DOI: 10.1007/s13105-026-01137-7
• EISSN: 1877-8755
• ISSN: 1138-7548
• Language: English
• Keywords: Arrhythmias; Catecholaminergic polymorphic ventricular tachycardia; CPVT; CASQ2; Calsequestrin 2
• Subtype: Review