Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 29, Pages 11881-11886Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1310571110
Keywords
dihydropyridine receptor; myopathy; dysgenic; dyspedic; neuromuscular junction
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Funding
- NIH [HL-077439, HL-093039, U01-HL-100401, AR-063182, T32-HL-007360]
- Welch Foundation [1-0025]
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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.
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