Journal
BIOPHYSICAL JOURNAL
Volume 87, Issue 5, Pages 3193-3204Publisher
CELL PRESS
DOI: 10.1529/biophysj.104.048447
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Funding
- NIAMS NIH HHS [R01 AR044657, R29 AR044657, AR44657] Funding Source: Medline
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Malignant hyperthermia (MH) and central core disease (CCD) are disorders of skeletal muscle Ca2(+) homeostasis that are linked to mutations in the type 1 ryanodine receptor (RyR1). Certain RyR1 mutations result in an MH-selective phenotype (MH-only), whereas others result in a mixed phenotype (MH+CCD). We characterized effects on Ca2+ handling and excitation-contraction (EC) coupling of MH-only and MH+CCD mutations in RyR1 after expression in skeletal myotubes derived from RyR1-null (dyspedic) mice. Compared to wild-type RyR1-expressing myotubes, MH+CCD- and MH-only-expressing myotubes exhibited voltage-gated Ca2+ release (VGCR) that activated at more negative potentials and displayed a significantly higher incidence of spontaneous Ca2+ oscillations. However, maximal VGCR was reduced only for MH+CCD mutants (Y4795C, R2435L, and R2163H) in which spontaneous Ca2+ oscillations occurred with significantly longer duration (Y4795C and R2435L) or higher frequency (R2163H). Notably, myotubes expressing these MH+CCD mutations in RyR1 exhibited both increased [Ca2+](i) and reduced sarcoplasmic reticulum (SR) Ca2+ content. We conclude that MH-only mutations modestly increase basal release-channel activity in a manner insufficient to alter net SR Ca2+ content (compensated leak''), whereas the mixed MH+CCD phenotype arises from mutations that enhance basal activity to a level sufficient to promote SR Ca2+ depletion, elevate [Ca2+](i), and reduce maximal VGCR (decompensated leak'').
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