Reduced threshold for store overload-induced Ca2+ release is a common defect of RyR1 mutations associated with malignant hyperthermia and central core disease

Chen, Wenqian; Koop, Andrea; Liu, Yingjie; Guo, Wenting; Wei, Jinhong; Wang, Ruiwu; MacLennan, David H.; Dirksen, Robert T.; Chen, Sui Rong Wayne

doi:10.1042/bcj20170282

Cited by 21 publications

(20 citation statements)

References 64 publications

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“…Interestingly, the threshold for SOICR is reduced in many disease-linked mutations of both RyR1 and RyR2. Moreover, this functional defect contributes to explaining the overactive behavior of the corresponding mutant proteins, along with the human symptoms of central core disease (CCD), malignant hyperthermia (MH), and catecholaminergic polymorphic ventricular tachycardia (CPVT) [97,101]. The molecular bases underlying SOICR are not yet entirely clear.…”

Section: Cardiac Ec Couplingmentioning

confidence: 99%

Ca2+ Channels Mediate Bidirectional Signaling between Sarcolemma and Sarcoplasmic Reticulum in Muscle Cells

Ávila

Rosa

Monsalvo-Villegas

et al. 2019

Cells

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The skeletal muscle and myocardial cells present highly specialized structures; for example, the close interaction between the sarcoplasmic reticulum (SR) and mitochondria—responsible for excitation-metabolism coupling—and the junction that connects the SR with T-tubules, critical for excitation-contraction (EC) coupling. The mechanisms that underlie EC coupling in these two cell types, however, are fundamentally distinct. They involve the differential expression of Ca2+ channel subtypes: CaV1.1 and RyR1 (skeletal), vs. CaV1.2 and RyR2 (cardiac). The CaV channels transform action potentials into elevations of cytosolic Ca2+, by activating RyRs and thus promoting SR Ca2+ release. The high levels of Ca2+, in turn, stimulate not only the contractile machinery but also the generation of mitochondrial reactive oxygen species (ROS). This forward signaling is reciprocally regulated by the following feedback mechanisms: Ca2+-dependent inactivation (of Ca2+ channels), the recruitment of Na+/Ca2+ exchanger activity, and oxidative changes in ion channels and transporters. Here, we summarize both well-established concepts and recent advances that have contributed to a better understanding of the molecular mechanisms involved in this bidirectional signaling.

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Section: Cardiac Ec Couplingmentioning

confidence: 99%

Ca2+ Channels Mediate Bidirectional Signaling between Sarcolemma and Sarcoplasmic Reticulum in Muscle Cells

Ávila

Rosa

Monsalvo-Villegas

et al. 2019

Cells

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“…wave was investigated. It was previously found that the activation of MHS causative RyR variant by halothane was dependent on the luminal SR Ca 2+ reaching above an 'storeoverload induced Ca 2+ release (SOICR) threshold' (Jiang et al, 2008;Chen et al, 2017).…”

Section: Propagation Of Ca 2+ Waves Is Dependent On the Luminal Sr Ca 2+mentioning

confidence: 99%

“…This suggests that even in conditions which favours CICR (by reducing competition by Mg 2+ ) the threshold required for Ca 2+ to activate the RyR1 cannot be met solely by a cytoplasmic propagating mechanism. It is also important to note that MHS RyR1 variants do not have an increased sensitivity to cytosolic Ca 2+ activation (Murayama et al, 2007;Chen et al, 2014;Chen et al, 2017).…”

Section: 'Classic' Cicr Does Not Contribute To Ryr1 Activation Duringmentioning

confidence: 99%

“…levels have been demonstrated to affect the propensity for the RyR to open in bilayer studies (Laver et al, 2004;Chen et al, 2014;Chen et al, 2017). Additional studies in MHS causative RyR variants have also demonstrated an increased sensitivity to luminal Ca 2+ activation, or alternatively described as having a reduced SOICR threshold (Jiang et al, 2008;Chen et al, 2017).…”

Section: Involvement Of Luminal Sr Ca 2+ During a Ca 2+ Wavementioning

confidence: 99%

“…The role of cytosolic Ca 2+ is still open to interpretation. As demonstrated in Chapter 4, it is possible that cytosolic Ca 2+ contributes to the 'pool' of Ca 2+ necessary for SOICR to occur (Chen et al, 2014;Chen et al, 2017).…”

Section: Chapter 6: Concluding Remarksmentioning

confidence: 99%

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Mechanisms of calcium handling during a malignant hyperthermia event.

Choi¹

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Malignant hyperthermia (MH) is a clinical syndrome of the skeletal muscle that presents as a hypermetabolic response to volatile gas anaesthetics such as halothane, isoflurane, and to the depolarizing muscle relaxant succinylcholine. Genetic predisposition mainly arises from mutations in the gene for skeletal muscle ryanodine receptor (RyR1); a calcium channel that is tightly regulated to release Ca 2+ for muscle contraction. MH susceptible RyR1 are more prone to open by RyR1 agonist, resulting in the uncontrolled release of Ca 2+ from the sarcoplasmic reticulum (SR). The hypermetabolic state is due to the excessive consumption of adenosine triphosphate (ATP) as the muscle works to clear the high cytosolic Ca 2+. Dantrolene has been used to great effect by clinicians in treating MH. However the mechanism of its action remains highly contested. This thesis examines Ca 2+ handling in muscle fibers where RyR1 activity is changed due to mutations. RyR1 activity was also acutely changed by altering the cytoplasmic environment and by treating the muscle fiber with varying RyR1 modulators. The release of SR Ca 2+ was monitored using fluorescent Ca 2+ indicators in mechanically skinned fibers isolated from rat, toad and human muscle susceptible to MH. The results show that the inhibitory effect of dantrolene is dependent on cytosolic concentrations of Mg 2+ ([Mg 2+ ]cyto), an endogenous negative regulator of the RyR1. Furthermore, it was demonstrated in human muscle susceptible to MH that dantrolene was ineffective at reducing halothane-induced Ca 2+ release in the presence of resting levels of [Mg 2+ ]cyto (1 mM). These results suggest that raised [Mg 2+ ]cyto, a condition which is likely to arise during an MH event, works synergistically with dantrolene to inhibit Ca 2+ release from the RyR1. It was also demonstrated that halothane induced Ca 2+ release took the form of a repetitive Ca 2+ wave in human MH, and toad muscle. A close examination of the release mechanism in human MH muscle revealed that the release of SR Ca 2+ and the mechanism underlying the propagation of the Ca 2+ wave was not due to Ca 2+-induced-Ca 2+-release (CICR). These results were contrasted to the observation made in toad skeletal muscle which showed the involvement of CICR. However, it was found that both luminal SR and cytosolic Ca 2+ plays an important role in the mechanisms involved in overactive Ca 2+ release. The demonstration of the Mg 2+ dependence on dantrolene inhibition of the RyR1 emphasized the importance of studying the RyR1 under near physiological conditions. Utilizing a novel approach by trapping Ca 2+ indicator in either the SR or the transverse tubule (t-system) of mechanically skinned rat skeletal muscle fibers, it was determined if Publications during candidature Choi RH, Koenig X & Launikonis BS. (2017). Dantrolene requires Mg 2+ to arrest malignant hyperthermia. Proceedings of the National Academy of Sciences 114, 4811-4815. Conference abstracts R.H. Choi, and B.S. Launikonis (2017). Dantrolene requires Mg 2+ to arrest mal...

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Limiting RyR2 open time prevents Alzheimer's disease‐related deficits in the 3xTG‐AD mouse model

Liu

Yao

Song

et al. 2021

J of Neuroscience Research

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Increasing evidence suggests that Alzheimer's disease (AD) progression is driven by a vicious cycle of soluble β‐amyloid (Aβ)‐induced neuronal hyperactivity. Thus, breaking this vicious cycle by suppressing neuronal hyperactivity may represent a logical approach to stopping AD progression. In support of this, we have recently shown that genetically and pharmacologically limiting ryanodine receptor 2 (RyR2) open time prevented neuronal hyperactivity, memory impairment, dendritic spine loss, and neuronal cell death in a rapid, early onset AD mouse model (5xFAD). Here, we assessed the impact of limiting RyR2 open time on AD‐related deficits in a relatively late occurring, slow developing AD mouse model (3xTG‐AD) that bears more resemblance (compared to 5xFAD) to that of human AD. Using behavioral tests, long‐term potentiation recordings, and Golgi and Nissl staining, we found that the RyR2‐E4872Q mutation, which markedly shortens the open duration of the RyR2 channel, prevented learning and memory impairment, defective long‐term potentiation, dendritic spine loss, and neuronal cell death in the 3xTG‐AD mice. Furthermore, pharmacologically shortening the RyR2 open time with R‐carvedilol rescued these AD‐related deficits in 3xTG mice. Therefore, limiting RyR2 open time may offer a promising, neuronal hyperactivity‐targeted anti‐AD strategy.

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Reduced threshold for store overload-induced Ca2+ release is a common defect of RyR1 mutations associated with malignant hyperthermia and central core disease

Cited by 21 publications

References 64 publications

Ca2+ Channels Mediate Bidirectional Signaling between Sarcolemma and Sarcoplasmic Reticulum in Muscle Cells

Ca2+ Channels Mediate Bidirectional Signaling between Sarcolemma and Sarcoplasmic Reticulum in Muscle Cells

Mechanisms of calcium handling during a malignant hyperthermia event.

Limiting RyR2 open time prevents Alzheimer's disease‐related deficits in the 3xTG‐AD mouse model

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