TY - JOUR
T1 - Skeletal muscle-specific T-tubule protein STAC3 mediates voltage-induced Ca2+ release and contractility
AU - Nelson, Benjamin R.
AU - Wu, Fenfen
AU - Liu, Yun
AU - Anderson, Douglas M.
AU - Mcanally, John
AU - Lin, Weichun
AU - Cannon, Stephen C.
AU - Bassel-Duby, Rhonda
AU - Olson, Eric N.
PY - 2013/7/16
Y1 - 2013/7/16
N2 - 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.
AB - 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.
KW - Dihydropyridine Receptor
KW - Dysgenic
KW - Dyspedic
KW - Myopathy
KW - Neuromuscular Junction
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U2 - 10.1073/pnas.1310571110
DO - 10.1073/pnas.1310571110
M3 - Article
C2 - 23818578
AN - SCOPUS:84880391617
SN - 0027-8424
VL - 110
SP - 11881
EP - 11886
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 29
ER -