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J. Biol. Chem., Vol. 276, Issue 17, 13810-13816, April 27, 2001
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From the As an inhibitor of Ca2+ release
through ryanodine receptor (RYR) channels, the skeletal muscle relaxant
dantrolene has proven to be both a valuable experimental probe of
intracellular Ca2+ signaling and a lifesaving treatment for
the pharmacogenetic disorder malignant hyperthermia. However,
the molecular basis and specificity of the actions of dantrolene on RYR
channels have remained in question. Here we utilize
[3H]ryanodine binding to further investigate the actions
of dantrolene on the three mammalian RYR isoforms. The inhibition of
the pig skeletal muscle RYR1 by dantrolene (10 µM) was
associated with a 3-fold increase in the Kd of
[3H]ryanodine binding to sarcoplasmic reticulum (SR)
vesicles such that dantrolene effectively reversed the 3-fold decrease
in the Kd for [3H]ryanodine binding
resulting from the malignant hyperthermia RYR1 Arg615
Dantrolene Inhibition of Ryanodine Receptor Ca2+
Release Channels
MOLECULAR MECHANISM AND ISOFORM SELECTIVITY*
,, and
Department of Biochemistry, Molecular
Biology, and Biophysics, University of Minnesota, Minneapolis,
Minnesota 55455 and the § Department of Physiology and
Biophysics, University of Calgary, Alberta, T2N 4N1, Canada
Cys mutation. Dantrolene inhibition of the RYR1 was dependent on the
presence of the adenine nucleotide and calmodulin and reflected a
selective decrease in the apparent affinity of RYR1 activation sites
for Ca2+ relative to Mg2+. In contrast to the
RYR1 isoform, the cardiac RYR2 isoform was unaffected by dantrolene,
both in native cardiac SR vesicles and when heterologously expressed in
HEK-293 cells. By comparison, the RYR3 isoform expressed in HEK-293
cells was significantly inhibited by dantrolene, and the extent of RYR3
inhibition was similar to that displayed by the RYR1 in native SR
vesicles. Our results thus indicate that both the RYR1 and the RYR3,
but not the RYR2, may be targets for dantrolene inhibition
in vivo.
*
This work was supported by grants from the American Heart
Association (to B. R. F.), Grant GM-31382 from the National
Institutes of Health (to C. F. L.), and grants from the Medical
Research Council and Heart and Stroke Foundation (to
S. R. W. C.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The 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: 6-155 Jackson
Hall, 321 Church St. S.E., Minneapolis, MN 55455. Tel.: 612-625-3292; Fax: 612-625-2163; E-mail: fruen001@tc.umn.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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