Isoform-specific structure and function of calsequestrin: Implications beyond calcium buffering in health and disease

Calsequestrin (CASQ) plays an important role in muscle contraction by buffering Ca2+ inside the sarcoplasmic reticulum (SR). Intriguingly, mammals express two CASQ isoforms encoded by separate genes with highly conserved protein structure. CASQ1 is mainly expressed in fast-twitch skeletal muscles; whereas CASQ2 predominates in slow-twitch muscles and heart. CASQ2 function is poorly defined in rhythmically beating heart where SR Ca2+-release is graded through Ca2+-induced Ca2+-release (CICR), compared to CASQ1 in skeletal muscle where Ca2+-release is all or none. A unique property of CASQ is that it can dynamically polymerize-depolymerize in Ca2+-concentration dependent manner. CASQ1 and CASQ2 not only differ in their polymerization properties but also interact with different RyR protein complexes at the junctional SR governing muscle fiber specific SR Ca2+-release. In recent years CASQ has gained renewed attention because mutations in CASQ1 and CASQ2 proteins cause cardiac and skeletal muscle disease, including malignant hyperthermia (skeletal muscle), cardiac arrhythmias and sudden cardiac death. Additionally studies have implicated that CASQ is more than a Ca2+-buffer and CASQ-dysfunction can affect mitochondrial function and Ca2+-entry via store operated Ca2+-entry. Therefore, the isoform specific functions of CASQ1 and CASQ2 in different striated muscles requires further investigation in the light of recent findings. This review explores what we have learned over last 30 years about CASQ and what gaps of knowledge still exist. Here, we discuss how structural divergence between CASQ1 and CASQ2, shape physio-pathological outcomes and highlight some of the recent findings that trigger renewed interest in CASQ proteins, including their role beyond Ca2+-buffering.