Voltage modulates halothane-triggered Ca2+ release in malignant hyperthermia-susceptible muscle

Zullo, Alberto; Textor, Martin; Elischer, Philipp; Mall, Stefan; Alt, Andreas; Klingler, Werner; Melzer, Werner

doi:10.1085/jgp.201711864

Cited by 12 publications

(8 citation statements)

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“…Since the first studies published by Hamilton and coworkers it was clear that the mutation causes an increased sensitivity of the RyR1 channel to caffeine, isoflurane, and temperature (Chelu et al, 2006; Durham et al, 2008). The Y522S mutation determines a shift of the voltage dependence of activation and inactivation of Ca 2+ release to more negative voltage compared to WT channel (Andronache et al, 2009; Zullo et al, 2018) and impairs the Ca 2+ -dependent inactivation of the release (Manno et al, 2013). The opening probability of RyR1 can be further increased by S -nitrosylation of several cysteines of RyR1 (Aracena-Parks et al, 2006; Sun et al, 2008, 2013).…”

Section: Introductionmentioning

confidence: 99%

Excessive Accumulation of Ca2 + in Mitochondria of Y522S-RYR1 Knock-in Mice: A Link Between Leak From the Sarcoplasmic Reticulum and Altered Redox State

et al. 2019

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Mice (Y522S or YS), carrying a mutation of the sarcoplasmic reticulum (SR) Ca2+ release channel of skeletal muscle fibers (ryanodine receptor type-1, RyR1) which causes Ca2+ leak, are a widely accepted and intensively studied model for human malignant hyperthermia (MH) susceptibility. Since the involvement of reactive oxygen species (ROS) and of mitochondria in MH crisis has been previously debated, here we sought to determine Ca2+ uptake in mitochondria and its possible link with ROS production in single fibers isolated from flexor digitorum brevis (FDB) of YS mice. We found that Ca2+ concentration in the mitochondrial matrix, as detected with the ratiometric FRET-based 4mtD3cpv probe, was higher in YS than in wild-type (WT) fibers at rest and after Ca2+ release from SR during repetitive electrical stimulation or caffeine administration. Also mitochondrial ROS production associated with contractile activity (detected with Mitosox probe) was much higher in YS fibers than in WT. Importantly, the inhibition of mitochondrial Ca2+ uptake achieved by silencing MCU reduced ROS accumulation in the matrix and Ca2+ release from SR. Finally, inhibition of mitochondrial ROS accumulation using Mitotempo reduced SR Ca2+ release in YS fibers exposed to caffeine. The present results support the view that mitochondria take up larger amounts of Ca2+ in YS than in WT fibers and that mitochondrial ROS production substantially contributes to the increased caffeine-sensitivity and to the enhanced Ca2+ release from SR in YS fibers.

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Section: Introductionmentioning

confidence: 99%

Excessive Accumulation of Ca2 + in Mitochondria of Y522S-RYR1 Knock-in Mice: A Link Between Leak From the Sarcoplasmic Reticulum and Altered Redox State

et al. 2019

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“… 35 , 36 Halothane's main effect on RyR1 is instead an increase in sensitivity to activation by voltage, 19 more marked in the RyR1 Y524S MH mouse than in the wild type. 19 This difference in sensitivity, compounded with the increased voltage sensitivity found in the YS and other animal models, 37 , 38 could be sufficient to explain the catastrophic MH reaction to halothane. 19 …”

Section: Discussionmentioning

confidence: 99%

“… 19 This difference in sensitivity, compounded with the increased voltage sensitivity found in the YS and other animal models, 37 , 38 could be sufficient to explain the catastrophic MH reaction to halothane. 19 …”

Section: Discussionmentioning

confidence: 99%

“…Caffeine is viewed as an enhancer of the sensitivity of RyR to activation by Ca 2+ ,17, 18 separate from the voltage-controlled EC coupling pathway,20, 34 a concept bolstered by the recent identification of a caffeine-binding site within a RyR1 cytosolic hub that also contains sites for Ca 2+ and activation-promoting ATP 35, 36. Halothane's main effect on RyR1 is instead an increase in sensitivity to activation by voltage, 19 more marked in the RyR1 Y524S MH mouse than in the wild type 19 . This difference in sensitivity, compounded with the increased voltage sensitivity found in the YS and other animal models,37, 38 could be sufficient to explain the catastrophic MH reaction to halothane 19 …”

Section: Discussionmentioning

confidence: 99%

“…We address primarily the HH group because we observed more muscle symptoms and signs in the absence of anaesthesia in our cohort compared with other MH-susceptible patients. Because caffeine and halothane enhance SR Ca 2+ release by different mechanisms, 17 , 18 , 19 , 20 the halothane sensitivity of the HH suggests a specific pathogenesis.…”

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confidence: 99%

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Abnormal calcium signalling and the caffeine–halothane contracture test

Figueroa

Kraeva

Manno

et al. 2019

British Journal of Anaesthesia

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BackgroundThe variable clinical presentation of malignant hyperthermia (MH), a disorder of calcium signalling, hinders its diagnosis and management. Diagnosis relies on the caffeine–halothane contracture test, measuring contraction forces upon exposure of muscle to caffeine or halothane (FC and FH, respectively). Patients with above-threshold FC or FH are diagnosed as MH susceptible. Many patients test positive to halothane only (termed ‘HH’). Our objective was to determine the characteristics of these HH patients, including their clinical symptoms and features of cytosolic Ca2+ signalling related to excitation–contraction coupling in myotubes.MethodsAfter institutional ethics committee approval, recruited patients undergoing contracture testing at Toronto's MH centre were assigned to three groups: HH, doubly positive (HS), and negative patients (HN). A clinical index was assembled from musculoskeletal symptoms and signs. An analogous calcium index summarised four measures in cultured myotubes: resting [Ca2+]cytosol, frequency of spontaneous cytosolic Ca2+ events, Ca2+ waves, and cell-wide Ca2+ spikes after electrical stimulation.ResultsThe highest values of both indexes were found in the HH group; the differences in calcium index between HH and the other groups were statistically significant. The principal component analysis confirmed the unique cell-level features of the HH group, and identified elevated resting [Ca2+]cytosol and spontaneous event frequency as the defining HH characteristics.ConclusionsThese findings suggest that HH pathogenesis stems from excess Ca2+ leak through sarcoplasmic reticulum channels. This identifies HH as a separate diagnostic group and opens their condition to treatment based on understanding of pathophysiological mechanisms.

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Overlapping Mechanisms of Exertional Heat Stroke and Malignant Hyperthermia: Evidence vs. Conjecture

2020

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Voltage modulates halothane-triggered Ca2+ release in malignant hyperthermia-susceptible muscle

Abstract: Malignant hyperthermia can result from mutations in the ryanodine receptor that favor anesthetic-induced Ca2+ release. Zullo et al. find that membrane potential modulates the effect of the volatile anesthetic halothane on skeletal muscle ryanodine receptors possessing the Y524S mutation.

Cited by 12 publications

References 65 publications

Excessive Accumulation of Ca2 + in Mitochondria of Y522S-RYR1 Knock-in Mice: A Link Between Leak From the Sarcoplasmic Reticulum and Altered Redox State

Excessive Accumulation of Ca2 + in Mitochondria of Y522S-RYR1 Knock-in Mice: A Link Between Leak From the Sarcoplasmic Reticulum and Altered Redox State

Abnormal calcium signalling and the caffeine–halothane contracture test

Overlapping Mechanisms of Exertional Heat Stroke and Malignant Hyperthermia: Evidence vs. Conjecture

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