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    Increased sensitivity of the ryanodine receptor to halothane-induced oligomerization in malignant hyperthermia-susceptible human skeletal muscle


    Glover, Louise and Heffron, James J.A. and Ohlendieck, Kay (2004) Increased sensitivity of the ryanodine receptor to halothane-induced oligomerization in malignant hyperthermia-susceptible human skeletal muscle. Journal of applied physiology, 96 (1). pp. 11-18. ISSN 8750-7587

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    Abstract

    Mutations in the skeletal muscle RyR1 isoform of the ryanodine receptor (RyR) Ca2+-release channel confer susceptibility to malignant hyperthermia, which may be triggered by inhalational anesthetics such as halothane. Using immunoblotting, we show here that the ryanodine receptor, calmodulin, junctin, calsequestrin, sarcalumenin, calreticulin, annexin-VI, sarco(endo)plasmic reticulum Ca2+-ATPase, and the dihydropyridine receptor exhibit no major changes in their expression level between normal human skeletal muscle and biopsies from individuals susceptible to malignant hyperthermia. In contrast, protein gel-shift studies with halothane-treated sarcoplasmic reticulum vesicles from normal and susceptible specimens showed a clear difference. Although the alpha2-dihydropyridine receptor and calsequestrin were not affected, clustering of the Ca2+-ATPase was induced at comparable halothane concentrations. In the concentration range of 0.014-0.35 mM halothane, anesthetic-induced oligomerization of the RyR1 complex was observed at a lower threshold concentration in the sarcoplasmic reticulum from patients with malignant hyperthermia. Thus the previously described decreased Ca2+-loading ability of the sarcoplasmic reticulum from susceptible muscle fibers is probably not due to a modified expression of Ca2+-handling elements, but more likely a feature of altered quaternary receptor structure or modified functional dynamics within the Ca2+-regulatory apparatus. Possibly increased RyR1 complex formation, in conjunction with decreased Ca2+ uptake, is of central importance to the development of a metabolic crisis in malignant hyperthermia.

    Item Type: Article
    Keywords: calcium homeostasis; excitation-contraction coupling; sarcoplasmic reticulum; supramolecular complex; triad;
    Academic Unit: Faculty of Science and Engineering > Biology
    Item ID: 7508
    Identification Number: https://doi.org/10.1152/japplphysiol.00537.2003
    Depositing User: Prof. Kay Ohlendieck
    Date Deposited: 14 Oct 2016 10:23
    Journal or Publication Title: Journal of applied physiology
    Publisher: American Physiological Society
    Refereed: Yes
    Funders: European Commission, Health Research Board (HRB)
    URI:

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