Transfection of Human Myoblasts with Mutated RYR1 Alters [Ca
نویسندگان
چکیده
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 Ca 2 1 homeostasis to mutations in the RYR1 cDNA has been obtained for few mutations. In this report, we show for the first time that cultured human skeletal muscle cells derived from MH-susceptible individuals exhibit a half-maximal halothane concentration causing an increase in intracellular Ca 2 1 concentration which is twofold lower than that of cells derived from MH-negative individuals. 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 Ca 2 1 transients elicited by halothane are concerned; on the other hand, overexpression of a mutated RYR1 Arg163Cys Ca 2 1 channel in muscle cells obtained from MH-negative individuals conveys hypersensitivity to halothane. Finally, our results show that the resting Ca 2 1 concentration of cultured skeletal muscle cells from MH-negative and MH-susceptible individuals is not significantly different. ( J. Clin. Invest. 1998. 101:1233–1242.)
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Diaz-Sylvester PL, Porta M, Copello JA. Halothane modulation of skeletal muscle ryanodine receptors: dependence on Ca , Mg , and ATP. Am J Physiol Cell Physiol 294: C1103–C1112, 2008. First published February 27, 2008; doi:10.1152/ajpcell.90642.2007.—Malignant hyperthermia (MH) susceptibility is a genetic disorder of skeletal muscle associated with mutations in the ryanodine receptor isoform 1 ...
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Malignant hyperthermia (MH) susceptibility is a genetic disorder of skeletal muscle associated with mutations in the ryanodine receptor isoform 1 (RyR1) of sarcoplasmic reticulum (SR). In MH-susceptible skeletal fibers, RyR1-mediated Ca(2+) release is highly sensitive to activation by the volatile anesthetic halothane. Indeed, studies with isolated RyR1 channels (using simple Cs(+) solutions) f...
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