RyR1 S-Nitrosylation Underlies Environmental Heat Stroke and Sudden Death in Y522S RyR1 Knockin Mice

William J. Durham, Paula Aracena-Parks, Cheng Long, Ann E. Rossi, Sanjeewa A. Goonasekera, Simona Boncompagni, Daniel L. Galvan, Charles P. Gilman, Mariah R. Baker, Natalia Shirokova, Feliciano Protasi, Robert Dirksen, Susan L. Hamilton

Research output: Contribution to journalArticlepeer-review

236 Scopus citations


Mice with a malignant hyperthermia mutation (Y522S) in the ryanodine receptor (RyR1) display muscle contractures, rhabdomyolysis, and death in response to elevated environmental temperatures. We demonstrate that this mutation in RyR1 causes Ca2+ leak, which drives increased generation of reactive nitrogen species (RNS). Subsequent S-nitrosylation of the mutant RyR1 increases its temperature sensitivity for activation, producing muscle contractures upon exposure to elevated temperatures. The Y522S mutation in humans is associated with central core disease. Many mitochondria in the muscle of heterozygous Y522S mice are swollen and misshapen. The mutant muscle displays decreased force production and increased mitochondrial lipid peroxidation with aging. Chronic treatment with N-acetylcysteine protects against mitochondrial oxidative damage and the decline in force generation. We propose a feed-forward cyclic mechanism that increases the temperature sensitivity of RyR1 activation and underlies heat stroke and sudden death. The cycle eventually produces a myopathy with damaged mitochondria.

Original languageEnglish (US)
Pages (from-to)53-65
Number of pages13
Issue number1
StatePublished - Apr 4 2008
Externally publishedYes



ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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