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J. Biol. Chem., Vol. 280, Issue 8, 6580-6587, February 25, 2005

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Dantrolene Stabilizes Domain Interactions within the Ryanodine Receptor^*

Shigeki Kobayashi, Mark L. Bannister, Jaya P. Gangopadhyay, Tomoyo Hamada, Jerome Parness, and Noriaki Ikemoto¶||

From the Boston Biomedical Research Institute, Watertown, Massachusetts 02472, the Departments of Anesthesia, Pharmacology, Pediatrics, and Physiology and Biophysics, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, and the ^¶Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115

Interdomain interactions between N-terminal and central domains serving as a "domain switch" are believed to be essential to the functional regulation of the skeletal muscle ryanodine receptor-1 Ca²⁺ channel. Mutational destabilization of the domain switch in malignant hyperthermia (MH), a genetic sensitivity to volatile anesthetics, causes functional instability of the channel. Dantrolene, a drug used to treat MH, binds to a region within this proposed domain switch. To explore its mechanism of action, the effect of dantrolene on MH-like channel activation by the synthetic domain peptide DP4 or anti-DP4 antibody was examined. A fluorescence probe, methylcoumarin acetate, was covalently attached to the domain switch using DP4 as a delivery vehicle. The magnitude of domain unzipping was determined from the accessibility of methylcoumarin acetate to a macromolecular fluorescence quencher. The Stern-Volmer quenching constant (K_Q) increased with the addition of DP4 or anti-DP4 antibody. This increase was reversed by dantrolene at both 37 and 22 °C and was unaffected by calmodulin. [³H]Ryanodine binding to the sarcoplasmic reticulum and activation of sarcoplasmic reticulum Ca²⁺ release, both measures of channel activation, were enhanced by DP4. These activities were inhibited by dantrolene at 37 °C, yet required the presence of calmodulin at 22 °C. These results suggest that the mechanism of action of dantrolene involves stabilization of domain-domain interactions within the domain switch, preventing domain unzipping-induced channel dysfunction. We suggest that temperature and calmodulin primarily affect the coupling between the domain switch and the downstream mechanism of regulation of Ca²⁺ channel opening rather than the domain switch itself.

Received for publication, July 23, 2004 , and in revised form, December 13, 2004.

^* This work was supported by NIAMS Grants AR16922 (to N. I.) and AR045593 (to J. P.) and NHLBI Grant HL072841 (to N. I.) from the National Institutes of Health and by the Banyu Fellowship Award in Cardiovascular Medicine (to S. K.). 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.

^|| To whom correspondence should be addressed: Boston Biomedical Research Inst., 64 Grove St., Watertown, MA 02472. Tel.: 617-658-7774; Fax: 617-972-1761; E-mail: ikemoto{at}bbri.org.

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