Why the study?
Does dantrolene require increased Mg2+ to arrest overactive Ca2+ release in human muscle models of malignant hyperthermia?
Does dantrolene require increased Mg2+ to arrest overactive Ca2+ release in human muscle models of malignant hyperthermia?
Dantrolene requires elevated Mg2+ levels, such as those produced by increased MgATP hydrolysis during a malignant hyperthermia episode, to effectively depress overactive Ca2+ release.
Suggests dantrolene efficacy in malignant hyperthermia may depend on elevated intracellular magnesium; leaves open.
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.
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Choi et al. (2017) studied this question.
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