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

## TL;DR

Calsequestrin 2 (CASQ2) regulates calcium in heart cells and its dysfunction causes arrhythmias, with new therapies targeting CASQ2 for precision cardiology.

## Contribution

This review integrates structural, functional, and pathological insights to position CASQ2 as a central target in arrhythmia and precision cardiology.

## Key findings

- CASQ2 dysfunction is linked to arrhythmias like CPVT and sudden cardiac death.
- CASQ2's structure and Ca2+ binding modulate cardiac Ca2+ dynamics and excitation-contraction coupling.
- New therapies aim to stabilize CASQ2 or target its gene expression for precision treatments.

## Abstract

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.

CASQ2 regulates Ca2+ storage and release in cardiac muscle through its structure and binding properties.

CASQ2 dysfunction contributes to arrhythmias like CPVT and sudden cardiac death.

New therapies aim to stabilize or modulate CASQ2 for precision heart treatments.