Malignant hyperthermia: An inherited disorder of skeletal muscle Ca2+ regulation

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscl e characterized by muscle contracture and life-threatening hypermetabolic c risis following exposure to halogenated anesthetics and depolarizing muscle relaxants during surgery. Susceptibility to MH results from mutations in C a2+ channel proteins that mediate excitation-contraction (EC) coupling, wit h the ryanodine receptor Ca2+ release channel (RyR1) representing the major locus. Here we review recent studies characterizing the effects of MH muta tions on the sensitivity of the RyR1 to drugs and endogenous channel effect ors including Ca2+ and calmodulin. In addition, we present a working model that incorporates these effects of MH mutations on the isolated RyR1 with t heir effects on the physiologic mechanism that activates Ca2+ release durin g EC coupling in intact muscle.