Abnormal sarcoplasmic reticulum ryanodine receptor in malignant hyperthermia

J. R. Mickelson, E. M. Gallant, L. A. Litterer, K. M. Johnson, W. E. Rempel, C. F. Louis

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Abstract

Previous studies have demonstrated that skeletal muscle from individuals susceptible to malignant hyperthermia (MH) has a defect associated with the mechanism of calcium release from its intracellular storage sites in the sarcoplasmic reticulum (SR). In this report we demonstrate that the [3H]ryanodine receptor of isolated MH-susceptible (MHS) porcine heavy SR exhibits an altered Ca2+ dependence of [3H]ryanodine binding at the low affinity Ca2+ site as well as a lower K(d) for ryanodine (92 versus 265 nM) when compared to normal porcine SR. The B(max) of the normal and MHS [3H]ryanodine receptor (9.3-12.6 pmol/mg) was not significantly different, and analysis of MHS and normal SR proteins by sodium dodecyl sulfate-polyacrylamide gel electrophoresis did not reveal a significant difference in the intensity of Coomassie Blue staining of the spanning protein/ryanodine receptor region of the gels (M(r) > 300,000). We also find that MHS porcine muscle intact fiber bundles exhibit a 5-10-fold lower ryanodine threshold for twitch and tetanus inhibition, and contracture onset when compared to normal muscle. Since the SR ryanodine receptor is a calcium release channel as well as a component intimately involved in transverse tubule-SR communication, abnormalities in the skeletal muscle ryanodine receptor may be responsible for the abnormal SR calcium release and contractile properties demonstrated by MHS muscle.

Original languageEnglish (US)
Pages (from-to)9310-9315
Number of pages6
JournalJournal of Biological Chemistry
Volume263
Issue number19
StatePublished - 1988

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