Dantrolene requires Mg 2+ to arrest malignant hyperthermia

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 transients elicited by MH triggers are unknown. Here, we show that Ca release in the absence of Mg is unaffected by the presence of dantrolene but that dantrolene becomes increasingly effective as cytoplasmic-free [Mg ] (free [Mg ] ) passes mM levels. Furthermore, we found in human muscle susceptible to MH that dantrolene was ineffective at reducing halothane-induced repetitive Ca waves in the presence of resting levels of free [Mg ] (1 mM). However, an increase of free [Mg ] to 1.5 mM could increase the period between Ca waves. These results reconcile previous contradictory reports in muscle fibers and isolated RyRs, where Mg is present or absent, respectively, and define the mechanism of action of dantrolene is to increase the Mg affinity of the RyR (or "stabilize" the resting state of the channel) and suggest that the accumulation of the metabolite Mg from MgATP hydrolysis is required to make dantrolene administration effective in arresting an MH episode.