The Journal of clinical investigation
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Malignant hyperthermia (MH) is a hypermetabolic disease triggered by volatile anesthetics and succinylcholine in genetically predisposed individuals. Nine point mutations in the skeletal muscle ryanodine receptor (RYR) gene have so far been identified and shown to correlate with the MH-susceptible phenotype, yet direct evidence linking abnormal Ca2+ homeostasis to mutations in the RYR1 cDNA has been obtained for few mutations. ⋯ We also present evidence demonstrating that overexpression of wild-type RYR1 in cells obtained from MH-susceptible individuals does not restore the MH-negative phenotype, as far as Ca2+ transients elicited by halothane are concerned; on the other hand, overexpression of a mutated RYR1 Arg163Cys Ca2+ channel in muscle cells obtained from MH-negative individuals conveys hypersensitivity to halothane. Finally, our results show that the resting Ca2+ concentration of cultured skeletal muscle cells from MH-negative and MH-susceptible individuals is not significantly different.