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TRANSLATIONAL PHYSIOLOGY

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

¹Department of Pharmacology, University College Dublin, Belfield, Dublin 4, Ireland; ²Irish Malignant Hyperthermia Diagnostic Centre, Department of Biochemistry, University College Cork, Cork, Ireland; and ³Department of Biology, National University of Ireland, Maynooth, County Kildare, Ireland

Submitted 20 May 2003 ; accepted in final form 2 September 2003

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 ₂-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.

calcium homeostasis; excitation-contraction coupling; sarcoplasmic reticulum; supramolecular complex; triad