Calsequestrin interacts directly with the cardiac ryanodine receptor luminal domain

Cardiac muscle contraction requires sarcoplasmic reticulum (SR) Ca²⁺ release mediated by the quaternary complex comprising the ryanodine receptor 2 (RyR2), calsequestrin 2 (CSQ2), junctin (encoded by ASPH) and triadin. Here, we demonstrate that a direct interaction exists between RyR2 and CSQ2. Topologically, CSQ2 binding occurs at the first luminal loop of RyR2. Co-expression of RyR2 and CSQ2 in a human cell line devoid of the other quaternary complex proteins results in altered Ca²⁺-release dynamics compared to cells expressing RyR2 only. These findings provide a new perspective for understanding the SR luminal Ca²⁺ sensor and its involvement in cardiac physiology and disease.