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

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.