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First published on January 2, 2008; DOI: 10.1124/mol.107.043299

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Received for publication November 9, 2007.
Revised December 22, 2007.
Accepted for publication December 31, 2007.

Enhanced Excitation-Coupled Calcium Entry (ECCE) in Myotubes Expressing Malignant Hyperthermia Mutation R163C is Attenuated by Dantrolene

Gennady Cherednichenko 1, Chris W Ward 2, Wei Feng 1, Elaine Cabrales 1, Luke Michaelson 2, Montserrat Samso 3, Jose R Lopez 3, Paul D Allen 3, Isaac N Pessah 1*

1 University of California 2 University of Maryland 3 Brigham and Women's Hospital

* Address correspondence to: E-mail: inpessah{at}ucdavis.edu

Abstract

Dantrolene is the drug of choice for the treatment 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 RyR1 R163C MH susceptibility mutation show significantly enhanced ECCE rates that could be restored to those measured in wild type (WT) 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.


Key words: Ion channel regulation, Ca imaging


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D. Jiang, W. Chen, J. Xiao, R. Wang, H. Kong, P. P. Jones, L. Zhang, B. Fruen, and S. R. W. Chen
Reduced Threshold for Luminal Ca2+ Activation of RyR1 Underlies a Causal Mechanism of Porcine Malignant Hyperthermia
J. Biol. Chem., July 25, 2008; 283(30): 20813 - 20820.
[Abstract] [Full Text] [PDF]


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