STIM2 regulates both intracellular Ca distribution and Ca movement in skeletal myotubes.

Stromal interaction molecule 1 (STIM1) along with Orai1 mediates extracellular Ca entry into the cytosol through a store-operated Ca entry (SOCE) mechanism in various tissues including skeletal muscle. However, the role(s) of STIM2, a homolog of STIM1, in skeletal muscle has not been well addressed. The present study, first, was focused on searching for STIM2-binding proteins from among proteins mediating skeletal muscle functions. This study used a binding assay, quadrupole time-of-flight mass spectrometry, and co-immunoprecipitation assay with bona-fide STIM2- and SERCA1a-expressing rabbit skeletal muscle. The region for amino acids from 453 to 729 of STIM2 binds to sarcoplasmic/endoplasmic reticulum Ca-ATPase 1a (SERCA1a). Next, oxalate-supported Ca-uptake experiments and various single-myotube Ca imaging experiments using STIM2-knockdown mouse primary skeletal myotubes have suggested that STIM2 attenuates SERCA1a activity during skeletal muscle contraction, which contributes to the intracellular Ca distribution between the cytosol and the SR at rest. In addition, STIM2 regulates Ca movement through RyR1 during skeletal muscle contraction as well as SOCE. Therefore, via regulation of SERCA1a activity, STIM2 regulates both intracellular Ca distribution and Ca movement in skeletal muscle, which makes it both similar to, yet different from, STIM1.