Dantrolene requires Mg 2+ to arrest malignant hyperthermia

Significance The nature of overactive Ca 2+ release in malignant hyperthermia (MH) and the mechanism of action of the drug dantrolene that arrests MH events are poorly understood. Here, we show that dantrolene stops overactive Ca 2+ release by increasing the affinity of the ryanodine receptor (RyR) to Mg 2+ . In particular, Ca 2+ waves induced by MH triggers in human muscle are not affected by dantrolene unless Mg 2+ increases above resting levels, a condition met by the increase in MgATP hydrolysis during an MH episode. We suggest that only the combination of dantrolene and increased Mg 2+ can depress overactive Ca 2+ release and the resulting excessive heat production to arrest MH.