Abstract
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.
Footnotes
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Supported by National Institute of Arthritis and Musculoskeletal and Skin Disease grants R01-AR43140 and P01-AR52354 (to P.D.A. and I.N.P.) and R03-AR053318 (to C.W.W.). Additional support was provided by the American Heart Association grant AHA0530147N (to M.S.).
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ABBREVIATIONS: MH, malignant hyperthermia; BLM, bilayer lipid membrane; EC, excitation-contraction; ECCE, excitation coupled calcium entry; FDB, flexor digitorum brevis; FKBP12, FK506 binding protein 12 kDa; RyR1, ryanodine receptor type 1; SR, sarcoplasmic reticulum; SOCE, store-operated calcium entry; τc, mean closed-dwell time; τo, mean open-dwell time; ES, electrical stimulation; WT, wild type; DP1, domain peptide 1; AA, amino acid; HET, heterozygous; HOM, homozygous; AM, acetoxymethyl ester; Mn-R, manganese-containing Ringer; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]propanesulfonate; PAGE, polyacrylamide gel electrophoresis; Ry, ryanodine.
- Received November 7, 2007.
- Accepted December 31, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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