Calsequestrin, a ~40 kD protein, binds Ca2+ with high capacity (40–50 mol Ca2+ mol−1 calsequestrin) but with moderate affinity (Kd = 1 mM) over a Ca2+ concentration range between 0.01 and 1 M and releases it with a high off-rate (106 s−1). A high concentration of calsequestrin (up to 100 mg mL−1) is present in the lumen of the junctional terminal cisternae of the sarcoplasmic reticulum (SR) (MacLennan and Chen 2009; Royer and Ríos 2009). In humans, there are two major isoforms; the skeletal muscle calsequestrin (Casq1) and the cardiac muscle calsequestrin (Casq2). They are encoded by casq1 and casq2 located on chromosomes 1q21 and 1p13.3-p11 and are the only isoforms in fast-twitch skeletal muscle and cardiac muscle, respectively. In slow-twitch skeletal muscle, Casq1 is the major isoform with Casq2 as minor. In general, the Ca2+-binding capacity of Casq2 is higher than that of Casq1. Isoforms of calsequestrin are also present in the endoplasmic...