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J. Biol. Chem., Vol. 283, Issue 30, 20813-20820, July 25, 2008

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Reduced Threshold for Luminal Ca²⁺ Activation of RyR1 Underlies a Causal Mechanism of Porcine Malignant Hyperthermia^*

Dawei Jiang¹, Wenqian Chen¹, Jianmin Xiao, Ruiwu Wang, Huihui Kong, Peter P. Jones, Lin Zhang, Bradley Fruen, and S. R. Wayne Chen²

From the Libin Cardiovascular Institutes of Alberta, Departments of Physiology and Biophysics and Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta T2N 4N1, Canada and the Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455

Naturally occurring mutations in the skeletal muscle Ca²⁺ release channel/ryanodine receptor RyR1 are linked to malignant hyperthermia (MH), a life-threatening complication of general anesthesia. Although it has long been recognized that MH results from uncontrolled or spontaneous Ca²⁺ release from the sarcoplasmic reticulum, how MH RyR1 mutations render the sarcoplasmic reticulum susceptible to volatile anesthetic-induced spontaneous Ca²⁺ release is unclear. Here we investigated the impact of the porcine MH mutation, R615C, the human equivalent of which also causes MH, on the intrinsic properties of the RyR1 channel and the propensity for spontaneous Ca²⁺ release during store Ca²⁺ overload, a process we refer to as store overload-induced Ca²⁺ release (SOICR). Single channel analyses revealed that the R615C mutation markedly enhanced the luminal Ca²⁺ activation of RyR1. Moreover, HEK293 cells expressing the R615C mutant displayed a reduced threshold for SOICR compared with cells expressing wild type RyR1. Furthermore, the MH-triggering agent, halothane, potentiated the response of RyR1 to luminal Ca²⁺ and SOICR. Conversely, dantrolene, an effective treatment for MH, suppressed SOICR in HEK293 cells expressing the R615C mutant, but not in cells expressing an RyR2 mutant. These data suggest that the R615C mutation confers MH susceptibility by reducing the threshold for luminal Ca²⁺ activation and SOICR, whereas volatile anesthetics trigger MH by further reducing the threshold, and dantrolene suppresses MH by increasing the SOICR threshold. Together, our data support a view in which altered luminal Ca²⁺ regulation of RyR1 represents a primary causal mechanism of MH.

Received for publication, March 11, 2008 , and in revised form, May 19, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants 1RO1HL75210 and RO1HL076433. This work was also supported by funds from the Canadian Institutes of Health Research (to S. R. W. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work. Recipients of the Alberta Heritage Foundation for Medical Research Studentship Award.

² Alberta Heritage Foundation for Medical Research Scientist. To whom correspondence should be addressed: 3330 Hospital Dr., NW, Calgary AB T2N 4N1, Canada. Tel.: 403-220-4235; E-mail: swchen{at}ucalgary.ca.

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