Defective Mg2+ regulation of RyR1 as a causal factor in malignant hyperthermia.
In skeletal muscle, Mg(2+) exerts a dual inhibitory effect on RyR1, by competing with Ca(2+) at the activation site and binding to a low affinity Ca(2+)/Mg(2+) inhibitory site. Pharmacological activators of RyR1 must overcome the inhibitory action of Mg(2+) before Ca(2+) efflux can occur. In normal muscle, where the free [Mg(2+)](i) is approximately 1mM, even prolonged exposure to millimolar levels of volatile anesthetics does not initiate SR Ca(2+) release. However, when the cytosolic [Mg(2+)] is reduced below the physiological range, low levels of volatile anesthetic within the clinically relevant range (1mM) can initiate SR Ca(2+) release, in the form of a propagating Ca(2+) wave. In human muscle fibers from malignant hyperthermia susceptible patients, such Ca(2+) waves occur when 1mM halothane is applied at physiological [Mg(2+)](i). There is increasing evidence to suggest that defective Mg(2+) regulation of RyR1 confers susceptibility to malignant hyperthermia. At the molecular level, interactions between critical RyR1 subdomains may explain the clustering of RyR1 mutations and associated effects on Mg(2+) regulation.
Steele
Derek S
DS
Institute of Membrane and Systems Biology, University of Leeds, Leeds LS29JT, UK. d.steele@leeds.ac.uk
Duke
Adrian M
AM
D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D006221:Halothane / Q000494:pharmacology; D006801:Humans; D008274:Magnesium / Q000378:metabolism / Q000502:physiology*; D008305:Malignant Hyperthermia / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000502:physiology*
D019837:Ryanodine Receptor Calcium Release Channel; D002110:Caffeine; D008274:Magnesium; D002118:Calcium; D006221:Halothane