Ryanodine receptors (RyRs), located in the endoplasmic reticulum (ER) membrane, are required for intracellular Ca 2þ release. Mutations in RyR1 can lead to severe genetic conditions that affect skeletal muscle, e.g., malignant hyperthermia (MH). More than 150 mutations in the RyR1 gene have been reported in MH patients. However, there were only a few experimental results confirming those mutations being responsible for the increment of the CICR sensitivities, since such a long cDNA of RyR1 not only required much complicated procedures for making desired mutations but also caused its low transfection efficiency of the mutant DNAs. We investigated properties of the RyR1 channels carrying disease-associated mutations at the N-terminal region. HEK293 cells expressing the mutant RyR1 channels exhibited alterations in Ca 2þ homeostasis, i.e., enhanced caffeine sensitivity, decrease of ER Ca 2þ contents, increases in resting cytoplasmic Ca 2þ concentration, changes in mitochondrial morphology, changes in pattern of electrostatic interaction. These results suggest that exploration of the functional mutations of RyR1 is probably effective in preventive diagnosis of patients associated with MH disease.
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