Calsequestrin-2 (CASQ2)

Calsequestrin-2 (CASQ2) is a high-capacity, low-affinity calcium-binding protein localized within the lumen of the sarcoplasmic reticulum (SR) in cardiac and slow-twitch skeletal muscle. It serves as the primary calcium reservoir, sequestering large amounts of calcium ions to maintain a high total SR calcium content while keeping the free calcium concentration low enough for efficient pump activity. Beyond its role as a buffer, CASQ2 acts as a luminal calcium sensor by forming a quaternary complex with the ryanodine receptor 2 (RyR2), triadin, and junctin, thereby modulating the opening of calcium release channels during the cardiac cycle. Loss-of-function mutations or deficiency in CASQ2 are the primary drivers of catecholaminergic polymorphic ventricular tachycardia type 2 (CPVT2), a severe arrhythmic disorder characterized by stress-induced sudden death. Because it is essential for calcium homeostasis, CASQ2 is a critical target for emerging therapies such as gene replacement and small molecule modulators designed to stabilize the SR calcium release complex. Furthermore, several common pharmaceuticals, including tricyclic antidepressants and certain antiarrhythmics, have been found to bind directly to CASQ2, potentially contributing to drug-induced cardiotoxicity and muscle dysfunction.

Other names

CASQ2Cardiac calsequestrinCalsequestrin, cardiac muscle isoformPDIB2Calsequestrin 2 (cardiac muscle)

Stabilization of the RyR2-CASQ2 complex to prevent diastolic calcium leak; Restoration of sarcoplasmic reticulum calcium buffering capacity; Viral-mediated gene replacement for CASQ2 deficiency.