Skeletal muscle-specific T-tubule protein STAC3 mediates voltage-induced Ca²⁺ release and contractility

Excitation-contraction (EC) coupling comprises events in muscle that convert electrical signals to Ca²⁺ transients, which then trigger contraction of the sarcomere. Defects in these processes cause a spectrum of muscle diseases. We report that STAC3, a skeletal muscle-specific protein that localizes to T tubules, is essential for coupling membrane depolarization to Ca²⁺ release from the sarcoplasmic reticulum (SR). Consequently, homozygous deletion of src homology 3 and cysteine rich domain 3 (Stac3) in mice results in complete paralysis and perinatal lethality with a range of musculoskeletal defects that reflect a blockade of EC coupling. Muscle contractility and Ca²⁺ release from the SR of cultured myotubes from Stac3 mutant mice could be restored by application of 4- chloro-m-cresol, a ryanodine receptor agonist, indicating that the sarcomeres, SR Ca²⁺ store, and ryanodine receptors are functional in Stac3 mutant skeletal muscle. These findings reveal a previously uncharacterized, but required, component of the EC coupling machinery of skeletal muscle and introduce a candidate for consideration in myopathic disorders.