RT Journal Article SR Electronic T1 Enhanced Excitation-Coupled Calcium Entry in Myotubes Expressing Malignant Hyperthermia Mutation R163C Is Attenuated by Dantrolene JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 1203 OP 1212 DO 10.1124/mol.107.043299 VO 73 IS 4 A1 Gennady Cherednichenko A1 Chris W. Ward A1 Wei Feng A1 Elaine Cabrales A1 Luke Michaelson A1 Montserrat Samso A1 José R. López A1 Paul D. Allen A1 Isaac N. Pessah YR 2008 UL http://molpharm.aspetjournals.org/content/73/4/1203.abstract AB 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. The American Society for Pharmacology and Experimental Therapeutics