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

BR Nelson, F Wu, Y Liu, DM Anderson… - Proceedings of the …, 2013 - National Acad Sciences
BR Nelson, F Wu, Y Liu, DM Anderson, J McAnally, W Lin, SC Cannon, R Bassel-Duby…
Proceedings of the National Academy of Sciences, 2013National Acad Sciences
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 …
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.
National Acad Sciences