Dantrolene requires Mg 2+ to arrest malignant hyperthermia
| العنوان: | Dantrolene requires Mg 2+ to arrest malignant hyperthermia |
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| المؤلفون: | Xaver Koenig, Bradley S. Launikonis, Rocky H. Choi |
| المصدر: | Proceedings of the National Academy of Sciences. 114:4811-4815 |
| بيانات النشر: | Proceedings of the National Academy of Sciences, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | inorganic chemicals, 0301 basic medicine, medicine.medical_specialty, Metabolite, Dantrolene, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, Calcium signaling, Multidisciplinary, Chemistry, Ryanodine receptor, Malignant hyperthermia, Skeletal muscle, medicine.disease, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, Mechanism of action, Anesthesia, medicine.symptom, Halothane, 030217 neurology & neurosurgery, medicine.drug |
| الوصف: | Malignant hyperthermia (MH) is a clinical syndrome of skeletal muscle that presents as a hypermetabolic response to volatile anesthetic gases, where susceptible persons may develop lethally high body temperatures. Genetic predisposition mainly arises from mutations on the skeletal muscle ryanodine receptor (RyR). Dantrolene is administered to alleviate MH symptoms, but its mechanism of action and its influence on the Ca2+ transients elicited by MH triggers are unknown. Here, we show that Ca2+ release in the absence of Mg2+ is unaffected by the presence of dantrolene but that dantrolene becomes increasingly effective as cytoplasmic-free [Mg2+] (free [Mg2+]cyto) passes mM levels. Furthermore, we found in human muscle susceptible to MH that dantrolene was ineffective at reducing halothane-induced repetitive Ca2+ waves in the presence of resting levels of free [Mg2+]cyto (1 mM). However, an increase of free [Mg2+]cyto to 1.5 mM could increase the period between Ca2+ waves. These results reconcile previous contradictory reports in muscle fibers and isolated RyRs, where Mg2+ is present or absent, respectively, and define the mechanism of action of dantrolene is to increase the Mg2+ affinity of the RyR (or "stabilize" the resting state of the channel) and suggest that the accumulation of the metabolite Mg2+ from MgATP hydrolysis is required to make dantrolene administration effective in arresting an MH episode. |
| تدمد: | 1091-6490 0027-8424 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::27a32e83ee30f4833474e682b0e018b3 https://doi.org/10.1073/pnas.1619835114 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi...........27a32e83ee30f4833474e682b0e018b3 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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