ArticleThe Journal of biological chemistry2008
Reduced threshold for luminal Ca2+ activation of RyR1 underlies a causal mechanism of porcine malignant hyperthermia.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 69 citations in OpenAlex.
- Safety profiles of sevoflurane in pediatric patients: a real-world pharmacovigilance assessment based on the FAERS database.Frontiers in pharmacology · 2025Article
- Detection of the T1640CVeterinarni medicina · 2023Article
- EuBiophysical journal · 2023Article
- Molecular Aspects Implicated in Dantrolene Selectivity with Respect to Ryanodine Receptor Isoforms.International journal of molecular sciences · 2023Article
- Mutations in proteins involved in E-C coupling and SOCE and congenital myopathies.The Journal of general physiology · 2022Review
- Heat-hypersensitive mutants of ryanodine receptor type 1 revealed by microscopic heating.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Effects of General Anesthetics on Synaptic Transmission and Plasticity.Current neuropharmacology · 2022Review
- Molecular Changes in the Cardiac RyR2 With Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT).Frontiers in physiology · 2022Article
- Pathological conformations of disease mutant Ryanodine Receptors revealed by cryo-EM.Nature communications · 2021Article
- 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
- Non-traumatic and non-drug-induced rhabdomyolysis.Archives of medical sciences. Atherosclerotic diseases · 2019Article
- Malignant hyperthermia, environmental heat stress, and intracellular calcium dysregulation in a mouse model expressing the p.G2435R variant of RYR1.British journal of anaesthesia · 2018Article
- Voltage modulates halothane-triggered CaThe Journal of general physiology · 2018Article
- Control of cardiac ryanodine receptor by sarcoplasmic reticulum luminal CaThe Journal of general physiology · 2017Review
- Reduced threshold for store overload-induced CaThe Biochemical journal · 2017Article
- Coupling of excitation to CaThe Journal of physiology · 2017Article
- Congenital myopathy results from misregulation of a muscle Ca2+ channel by mutant Stac3.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- [Malignant hyperthermia syndrome in the intensive care unit : Differential diagnosis and acute measures].Medizinische Klinik, Intensivmedizin und Notfallmedizin · 2016Review
- Malignant hyperthermia: a review.Orphanet journal of rare diseases · 2015Review
- Article
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
Naturally occurring mutations in the skeletal muscle Ca(2+) release channel/ryanodine receptor RyR1 are linked to malignant hyperthermia (MH), a life-threatening complication of general anesthesia. Although it has long been recognized that MH results from uncontrolled or spontaneous Ca(2+) release from the sarcoplasmic reticulum, how MH RyR1 mutations render the sarcoplasmic reticulum susceptible to volatile anesthetic-induced spontaneous Ca(2+) release is unclear. Here we investigated the impact of the porcine MH mutation, R615C, the human equivalent of which also causes MH, on the intrinsic properties of the RyR1 channel and the propensity for spontaneous Ca(2+) release during store Ca(2+) overload, a process we refer to as store overload-induced Ca(2+) release (SOICR). Single channel analyses revealed that the R615C mutation markedly enhanced the luminal Ca(2+) activation of RyR1. Moreover, HEK293 cells expressing the R615C mutant displayed a reduced threshold for SOICR compared with cells expressing wild type RyR1. Furthermore, the MH-triggering agent, halothane, potentiated the response of RyR1 to luminal Ca(2+) and SOICR. Conversely, dantrolene, an effective treatment for MH, suppressed SOICR in HEK293 cells expressing the R615C mutant, but not in cells expressing an RyR2 mutant. These data suggest that the R615C mutation confers MH susceptibility by reducing the threshold for luminal Ca(2+) activation and SOICR, whereas volatile anesthetics trigger MH by further reducing the threshold, and dantrolene suppresses MH by increasing the SOICR threshold. Together, our data support a view in which altered luminal Ca(2+) regulation of RyR1 represents a primary causal mechanism of MH.
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