Azumolene inhibits a component of store-operated calcium entry coupled to the skeletal muscle ryanodine receptor.
Dantrolene reduces the elevated myoplasmic Ca(2+) generated during malignant hyperthermia, a pharmacogenetic crisis triggered by volatile anesthetics. Although specific binding of dantrolene to the type 1 ryanodine receptor (RyR1), the Ca(2+) release channel of skeletal muscle sarcoplasmic reticulum, has been demonstrated, there is little evidence for direct dantrolene inhibition of RyR1 channel function. Recent studies suggest store-operated Ca(2+) entry (SOCE) contributes to skeletal muscle function, but the effect of dantrolene on this pathway has not been examined. Here we show that azumolene, an equipotent dantrolene analog, inhibits a component of SOCE coupled to activation of RyR1 by caffeine and ryanodine, whereas the SOCE component induced by thapsigargin is not affected. Our data suggest that azumolene distinguishes between two mechanisms of cellular signaling to SOCE in skeletal muscle, one that is coupled to and one independent from RyR1.
Zhao
Xiaoli
X
Department of Physiology and Biophysics, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854, USA.
Weisleder
Noah
N
Han
Xuehai
X
Pan
Zui
Z
Parness
Jerome
J
Brotto
Marco
M
Ma
Jianjie
J
D000375:Aging / Q000502:physiology; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism*; D006224:Cricetinae; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D010080:Oxazoles / Q000494:pharmacology*; D011485:Protein Binding; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*; D019284:Thapsigargin / Q000494:pharmacology
D007093:Imidazoles; D010080:Oxazoles; D019837:Ryanodine Receptor Calcium Release Channel; C061387:azumolene; D019284:Thapsigargin; D002118:Calcium