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Volume 272, Number 43, Issue of October 24, 1997 pp. 26965-26971
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Dantrolene Inhibition of Sarcoplasmic Reticulum Ca²⁺ Release by Direct and Specific Action at Skeletal Muscle Ryanodine Receptors

(Received for publication, July 10, 1997, and in revised form, August 18, 1997)

From the Departments of Veterinary PathoBiology and ^§ Biochemistry, University of Minnesota, St. Paul, Minnesota 55108

The skeletal muscle relaxant dantrolene inhibits the release of Ca²⁺ from the sarcoplasmic reticulum during excitation-contraction coupling and suppresses the uncontrolled Ca²⁺ release that underlies the skeletal muscle pharmacogenetic disorder malignant hyperthermia; however, the molecular mechanism by which dantrolene selectively affects skeletal muscle Ca²⁺ regulation remains to be defined. Here we provide evidence of a high-affinity, monophasic inhibition by dantrolene of ryanodine receptor Ca²⁺ channel function in isolated sarcoplasmic reticulum vesicles prepared from malignant hyperthermia-susceptible and normal pig skeletal muscle. In media simulating resting myoplasm, dantrolene increased the half-time for ⁴⁵Ca²⁺ release from both malignant hyperthermia and normal vesicles approximately 3.5-fold and inhibited sarcoplasmic reticulum vesicle [³H]ryanodine binding (K_i ~150 nM for both malignant hyperthermia and normal). Inhibition of vesicle [³H]ryanodine binding by dantrolene was associated with a decrease in the extent of activation by both calmodulin and Ca²⁺. Dantrolene also inhibited [³H]ryanodine binding to purified skeletal muscle ryanodine receptor protein reconstituted into liposomes. In contrast, cardiac sarcoplasmic reticulum vesicle ⁴⁵Ca²⁺ release and [³H]ryanodine binding were unaffected by dantrolene. Together, these results demonstrate selective effects of dantrolene on skeletal muscle ryanodine receptors that are consistent with the actions of dantrolene in vivo and suggest a mechanism of action in which dantrolene may act directly at the skeletal muscle ryanodine receptor complex to limit its activation by calmodulin and Ca²⁺. The potential implications of these results for understanding how dantrolene and malignant hyperthermia mutations may affect the voltage-dependent activation of Ca²⁺ release in intact skeletal muscle are discussed.

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