Malignant Hyperthermia: An Inherited Disorder of Skeletal Muscle Ca2+ Regulation

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle characterized by muscle contracture and life-threatening hypermetabolic crisis following exposure to halogenated anesthetics and depolarizing muscle relaxants during surgery. Susceptibility to MH results from mutations in Ca²⁺ channel proteins that mediate excitation–contraction (EC) coupling, with the ryanodine receptor Ca²⁺ release channel (RyR1) representing the major locus. Here we review recent studies characterizing the effects of MH mutations on the sensitivity of the RyR1 to drugs and endogenous channel effectors including Ca²⁺ and calmodulin. In addition, we present a working model that incorporates these effects of MH mutations on the isolated RyR1 with their effects on the physiologic mechanism that activates Ca²⁺ release during EC coupling in intact muscle.