Résumé
Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle triggered in susceptible individuals by inhalation anesthetics and depolarizing skeletal muscle relaxants. This syndrome has been linked to a missense mutation in the type 1 ryanodine receptor (RyR1) in more than 50% of cases studied to date. Using double-barreled ...microelectrodes in myotubes expressing wild-type RyR1 (...) or RyR1 with one of four common MH mutations (...), we measured resting intracellular ... concentration (...). Changes in resting ... produced by several drugs known to modulate the RyR1 channel complex were investigated. We found that myotubes expressing any of the ... had a 2.0- to 3.7-fold higher resting ... than those expressing ... Exposure of myotubes expressing ... to ryanodine (...) or (2,6-dichloro-4-aminophenyl)isopropylamine (FLA 365; 20 ...M) had no effects on their resting ... However, when myotubes were exposed to bastadin S alone or to a combination of ryanodine and bastadin 5, the resting ... was significantly reduced (P < 0.01). Interestingly, the percent decrease in resting ... in myotubes expressing ... was significantly greater than that for ... From these data, we propose that the high resting myoplasmic ... in ... expressing myotubes is due in part to a related structural conformation of ... s that favors "passive" calcium leak from the sarcoplasmic reticulum. (ProQuest-CSA LLC: ... denotes formulae/symbols omitted.)