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 Ca super(2+) microelectrodes in myotubes expressing wild-type RyR1 ( sub(WT)RyR1) or RyR1 with one of four common MH mutations ( sub(MH)RyR1), we measured resting intracellular Ca super(2+) concentration ([Ca super(2+)] sub(i)). Changes in resting [Ca super(2+)] sub(i) produced by several drugs known to modulate the RyR1 channel complex were investigated. We found that myotubes expressing any of the sub(MH)RyR1s had a 2.0- to 3.7-fold higher resting [Ca super(2+)] sub(i) than those expressing sub(WT)RyR1. Exposure of myotubes expressing sub(MH)RyR1s to ryanodine (500 mu M) or (2,6-dichloro-4-aminophenyl)isopropylamine (FLA 365; 20 mu M) had no effects on their resting [Ca super(2+)] sub(i). However, when myotubes were exposed to bastadin 5 alone or to a combination of ryanodine and bastadin 5, the resting [Ca super(2+)] sub(i) was significantly reduced (P < 0.01). Interestingly, the percent decrease in resting [Ca super(2+)] sub(i) in myotubes expressing sub(MH)RyR1s was significantly greater than that for sub(WT)RyR1. From these data, we propose that the high resting myoplasmic [Ca super(2+)] sub(i) in sub(MH)RyR1 expressing myotubes is due in part to a related structural conformation of sub(MH)RyR1s that favors "passive" calcium leak from the sarcoplasmic reticulum.