Dantrolene requires Mg2+ to arrest malignant hyperthermia

Choi, Rocky H., Koenig, Xaver and Launikonis, Bradley S. (2017) Dantrolene requires Mg2+ to arrest malignant hyperthermia. Proceedings of the National Academy of Sciences of the United States of America, 114 18: 4811-4815. doi:10.1073/pnas.1619835114


Author Choi, Rocky H.
Koenig, Xaver
Launikonis, Bradley S.
Title Dantrolene requires Mg2+ to arrest malignant hyperthermia
Formatted title
Dantrolene requires Mg2+ to arrest malignant hyperthermia
Journal name Proceedings of the National Academy of Sciences of the United States of America   Check publisher's open access policy
ISSN 1091-6490
0027-8424
Publication date 2017-05-02
Sub-type Article (original research)
DOI 10.1073/pnas.1619835114
Open Access Status Not yet assessed
Volume 114
Issue 18
Start page 4811
End page 4815
Total pages 5
Place of publication Washington, DC, United States
Publisher National Academy of Sciences
Language eng
Abstract 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 Ca(2+) transients elicited by MH triggers are unknown. Here, we show that Ca(2+) release in the absence of Mg(2+) is unaffected by the presence of dantrolene but that dantrolene becomes increasingly effective as cytoplasmic-free [Mg(2+)] (free [Mg(2+)]cyto) passes mM levels. Furthermore, we found in human muscle susceptible to MH that dantrolene was ineffective at reducing halothane-induced repetitive Ca(2+) waves in the presence of resting levels of free [Mg(2+)]cyto (1 mM). However, an increase of free [Mg(2+)]cyto to 1.5 mM could increase the period between Ca(2+) waves. These results reconcile previous contradictory reports in muscle fibers and isolated RyRs, where Mg(2+) is present or absent, respectively, and define the mechanism of action of dantrolene is to increase the Mg(2+) affinity of the RyR (or "stabilize" the resting state of the channel) and suggest that the accumulation of the metabolite Mg(2+) from MgATP hydrolysis is required to make dantrolene administration effective in arresting an MH episode.
Formatted abstract
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 mMlevels. 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.
Keyword Dantrolene
Magnesium
Malignant hyperthermia
Ryanodine receptor
Skeletal muscle fiber
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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