Abnormal sarcoplasmic reticulum ryanodine receptor in malignant hyperthermia.
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 Kd for ryanodine (92 versus 265 nM) when compared to normal porcine SR. The Bmax 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 (Mr greater than 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.
Mickelson
J R
JR
Department of Veterinary Biology, University of Minnesota, St. Paul 55108.
Gallant
E M
EM
Litterer
L A
LA
Johnson
K M
KM
Rempel
W E
WE
Louis
C F
CF
D000470:Alkaloids / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D007700:Kinetics; D008305:Malignant Hyperthermia / Q000378:metabolism*; D009132:Muscles / Q000378:metabolism*; D011950:Receptors, Cholinergic / Q000378:metabolism*; D012016:Reference Values; D012433:Ryanodine / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D013552:Swine
D000470:Alkaloids; D011950:Receptors, Cholinergic; D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine; D002118:Calcium