Calsequestrin: a well-known but curious protein in skeletal muscle

Calsequestrin (CASQ) was discovered in rabbit skeletal muscle tissues in 1971 and has been considered simply a passive Ca 2+ -buffering protein in the sarcoplasmic reticulum (SR) that provides Ca 2+ ions for various Ca 2+ signals. For the past three decades, physiologists, biochemists, and structural biologists have examined the roles of the skeletal muscle type of CASQ (CASQ1) in skeletal muscle and revealed that CASQ1 has various important functions as (1) a major Ca 2+ -buffering protein to maintain the SR with a suitable amount of Ca 2+ at each moment, (2) a dynamic Ca 2+ sensor in the SR that regulates Ca 2+ release from the SR to the cytosol, (3) a structural regulator for the proper formation of terminal cisternae, (4) a reverse-directional regulator of extracellular Ca 2+ entries, and (5) a cause of human skeletal muscle diseases. This review is focused on understanding these functions of CASQ1 in the physiological or pathophysiological status of skeletal muscle. Muscle function: Multiple roles for a muscle modulator Although previously considered merely a passive regulator of calcium levels, the protein calsequestrin is now known to perform a range of physiological activities essential to skeletal muscle function. The process of muscle contraction depends on the release of calcium ions from an intracellular structure called the sarcoplasmic reticulum (SR). Calsequestrin was originally identified as a “buffering” factor that maintains adequate calcium reserves in the SR, but Eun Hui Lee and colleagues at the Catholic University of Korea review diverse functions that have since been ascribed to this protein. For example, calsequestrin also helps reinforce the structure of the SR, and actively regulates the flux of calcium ions into muscle cells. Perturbations in calsequestrin function also appear to contribute to a number of muscular disorders, including a potential link to Duchenne muscular dystrophy.