Enhanced excitation-coupled calcium entry in myotubes expressing malignant hyperthermia mutation R163C is attenuated by dantrolene.
Dantrolene is the drug of choice for the treatment of malignant hyperthermia (MH) and is also useful for treatment of spasticity or muscle spasms associated with several clinical conditions. The current study examines the mechanisms of dantrolene's action on skeletal muscle and shows that one of dantrolene's mechanisms of action is to block excitation-coupled calcium entry (ECCE) in both adult mouse flexor digitorum brevis fibers and primary myotubes. A second important new finding is that myotubes isolated from mice heterozygous and homozygous for the ryanodine receptor type 1 R163C MH susceptibility mutation show significantly enhanced ECCE rates that could be restored to those measured in wild-type cells after exposure to clinical concentrations of dantrolene. We propose that this gain of ECCE function is an important etiological component of MH susceptibility and possibly contributes to the fulminant MH episode. The inhibitory potency of dantrolene on ECCE found in wild-type and MH-susceptible muscle is consistent with the drug's clinical potency for reversing the MH syndrome and is incomplete as predicted by its efficacy as a muscle relaxant.
Cherednichenko
Gennady
G
Department of Molecular Biosciences, School of Veterinary Medicine, One Shields Avenue, University of California, Davis, CA 95616, USA.
Ward
Chris W
CW
Feng
Wei
W
Cabrales
Elaine
E
Michaelson
Luke
L
Samso
Montserrat
M
López
José R
JR
Allen
Paul D
PD
Pessah
Isaac N
IN
D019943:Amino Acid Substitution; D000818:Animals; D000831:Animals, Newborn; D001120:Arginine / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D003545:Cysteine / Q000235:genetics; D003620:Dantrolene / Q000494:pharmacology*; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008305:Malignant Hyperthermia / Q000235:genetics*; D008564:Membrane Potentials / Q000187:drug effects; D008567:Membranes, Artificial; D051379:Mice; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D009125:Muscle Relaxants, Central / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D011189:Potassium Chloride / Q000494:pharmacology; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism
D008567:Membranes, Artificial; D009125:Muscle Relaxants, Central; D050505:Mutant Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D011189:Potassium Chloride; D001120:Arginine; D003620:Dantrolene; D003545:Cysteine; D002118:Calcium