Fig. 1. Scheme of the subcellular structures involved in excitation-contraction coupling of skeletal muscle. The dihydropyridine receptor senses the membrane depolarization, alters its conformation, and activates the ryanodine receptor (which releases Ca2+from the sarcoplasmic reticulum [SR], a Ca2+store). Ca2+binds to troponin and activates the so-called contractile machinery. Interstitial and SR-luminal calcium concentrations are in the millimolar range, whereas the myoplasmic Ca2+concentration at rest is in the upper nanomolar to low micromolar range. The large Ca2+gradients are maintained by the SR Ca2+pump and indirectly by the sarcolemmal Na+/K+pump (the Na+gradient drives the Na+/Ca2+exchanger). In classic malignant hyperthermia, uncontrolled Ca2+release from the SR leads to an increased pump activity and heat production, mainly by the adenosine triphosphate-dependent Ca2+reuptake into the SR. To cope with the increased energy consumption, glycogen stores will be depleted for maximal adenosine triphosphate production. The myoplasmic Ca2+overload may also stimulate Ca2+sensitive proteases, liposomal enzymes, and nuclear DNases, potentially resulting in rhabdomyolysis.