ArticleThe Journal of physiology2013
Altered Ca2+ concentration, permeability and buffering in the myofibre Ca2+ store of a mouse model of malignant hyperthermia.
Article in The Journal of physiology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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21 citing papers in PubMed, 29 citations in OpenAlex.
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- Molecular mechanism of the severe MH/CCD mutation Y522S in skeletal ryanodine receptor (RyR1) by cryo-EM.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Altered CaMetabolites · 2021Review
- Adaptive thermogenesis enhances the life-threatening response to heat in mice with an Ryr1 mutation.Nature communications · 2020Article
- Pre-assembled Ca2+ entry units and constitutively active Ca2+ entry in skeletal muscle of calsequestrin-1 knockout mice.The Journal of general physiology · 2020Article
- Structural mechanism of two gain-of-function cardiac and skeletal RyR mutations at an equivalent site by cryo-EM.Science advances · 2020Article
- Preclinical model systems of ryanodine receptor 1-related myopathies and malignant hyperthermia: a comprehensive scoping review of works published 1990-2019.Orphanet journal of rare diseases · 2020Article
- CaATP prolongs strong actomyosin binding and promotes futile myosin stroke.Journal of muscle research and cell motility · 2019Article
- Excessive Accumulation of CaFrontiers in physiology · 2019Article
- Role of STIM1/ORAI1-mediated store-operated CaCell calcium · 2018Review
- Calcium-induced release of calcium in muscle: 50 years of work and the emerging consensus.The Journal of general physiology · 2018Review
- Voltage modulates halothane-triggered CaThe Journal of general physiology · 2018Article
- Reduced threshold for store overload-induced CaThe Biochemical journal · 2017Article
- Dampened activity of ryanodine receptor channels in mutant skeletal muscle lacking TRIC-A.The Journal of physiology · 2017Article
- The disorders of the calcium release unit of skeletal muscles: what have we learned from mouse models?Journal of muscle research and cell motility · 2015Review
- Article
- Activation and propagation of Ca2+ release from inside the sarcoplasmic reticulum network of mammalian skeletal muscle.The Journal of physiology · 2014Article
- Ca2+ influx via the Na+/Ca2+ exchanger is enhanced in malignant hyperthermia skeletal muscle.The Journal of biological chemistry · 2014Article
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11 authors at 4 institutions in 2 countries.
Funding
Abstract
Malignant hyperthermia (MH) is linked to mutations in the type 1 ryanodine receptor, RyR1, the Ca2+ channel of the sarcoplasmic reticulum (SR) of skeletal muscle. The Y522S MH mutation was studied for its complex presentation, which includes structurally and functionally altered cell 'cores'. Imaging cytosolic and intra-SR [Ca2+] in muscle cells of heterozygous YS mice we determined Ca2+ release flux activated by clamp depolarization, permeability (P) of the SR membrane (ratio of flux and [Ca2+] gradient) and SR Ca2+ buffering power (B). In YS cells resting [Ca2+]SR was 45% of the value in normal littermates (WT). P was more than doubled, so that initial flux was normal. Measuring [Ca2+]SR(t) revealed dynamic changes in B(t). The alterations were similar to those caused by cytosolic BAPTA, which promotes release by hampering Ca2+-dependent inactivation (CDI). The [Ca2+] transients showed abnormal 'breaks', decaying phases after an initial rise, traced to a collapse in flux and P. Similar breaks occurred in WT myofibres with calsequestrin reduced by siRNA; calsequestrin content, however, was normal in YS muscle. Thus, the Y522S mutation causes greater openness of the RyR1, lowers resting [Ca2+]SR and alters SR Ca2+ buffering in a way that copies the functional instability observed upon reduction of calsequestrin content. The similarities with the effects of BAPTA suggest that the mutation, occurring near the cytosolic vestibule of the channel, reduces CDI as one of its primary effects. The unstable SR buffering, mimicked by silencing of calsequestrin, may help precipitate the loss of Ca2+ control that defines a fulminant MH event.
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