Mind the magnesium, in dantrolene suppression of malignant hyperthermia.

Malignant hyperthermia (MH) is a pharmacogenetic syndrome wherein exposure to halogenated volatile anesthetics or to depolarizing muscle relaxants during general anesthesia may trigger a life-threatening hypermetabolic state driven by excessive Ca release from the sarcoplasmic reticulum (SR) of skeletal muscle (1). Over 25 y ago, the acute administration of dantrolene was shown to be highly effective at aborting an episode of MH (2), but the mechanism and site of action have been incompletely resolved because of conflicting reports on the ability of dantrolene to inhibit the SR Ca release channel (RyR1) in different experimental preparations (3, 4). In PNAS, Choi et al. from the Launikonis laboratory in Queensland, Australia, now provide evidence in skinned muscle fibers from rat that inhibition of SR Ca release by dantrolene is Mg-dependent, and that suppression of halothane or caffeine-induced Ca waves in human MH muscle requires an elevation of Mg above basal levels (5). These observations offer a mechanism to reconcile conflicting reports on whether dantrolene is able to inhibit RyR1 in reductionist experimental systems, and suggest that a modest degree of metabolic stress, sufficient to reduce local [ATP] and release Mg, is required for the drug to suppress an impending episode of MH.