Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024591 (malignant hyperthermia)
 2,353 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malignant hyperthermia (MH) and central core disease (CCD) mutations were introduced into full-length rabbit Ca2+ release channel (RYR1) cDNA, which was then expressed transiently in HEK-293 cells. Resting Ca2+ concentrations were higher in HEK-293 cells expressing homotetrameric CCD mutant RyR1 than in cells expressing homotetrameric MH mutant RyR1. Cells expressing homotetrameric CCD or MH mutant RyR1 exhibited lower maximal peak amplitudes of caffeine-induced Ca2+ release than cells expressing wild type RyR1, suggesting that MH and CCD mutants might be "leaky." In cells expressing homotetrameric wild type or mutant RyR1, the amplitude of 10 mM caffeine-induced Ca2+ release was correlated significantly with the amplitude of carbachol- or thapsigargin-induced Ca2+ release, indicating that maximal drug-induced Ca2+ release depends on the size of the endoplasmic reticulum Ca2+ store. The content of endogenous sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2b (SERCA2b), measured by enzyme-linked immunosorbent assay, 45Ca2+ uptake, and confocal microscopy, was increased in HEK-293 cells expressing wild type or mutant RyR1, supporting the view that endoplasmic reticulum Ca2+ storage capacity is increased as a compensatory response to an enhanced Ca2+ leak. When heterotetrameric (1:1) combinations of MH/CCD mutant and wild type RyR1 were expressed together with SERCA1 to enhance Ca2+ reuptake, the amplitude of Ca2+ release in response to low concentrations of caffeine and halothane was higher than that observed in cells expressing wild type RyR1 and SERCA1. In Ca2+-free medium, MH/CCD mutants were more sensitive to caffeine than wild type RyR1, indicating that caffeine hypersensitivity observed with a variety of MH/CCD mutant RyR1 proteins is not dependent on extracellular Ca2+ concentration.
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PMID:Measurement of resting cytosolic Ca2+ concentrations and Ca2+ store size in HEK-293 cells transfected with malignant hyperthermia or central core disease mutant Ca2+ release channels. 987 4

The mechanism of action of volatile anesthetics is not completely understood. Calcium release from internal stores may alter signaling pathways that influence neurotransmission. Abnormalities of the regulation of intracellular calcium concentration ([Ca2+]i) from patients with malignant hyperthermia is a hallmark of this syndrome indicating the potential of these agents to interact with proteins involved in Ca2+ signaling. In the present study, a cholinergic cell line (SN56) was used to examine whether the release of calcium from intracellular stores occurs in the presence of sevoflurane. Changes in [Ca2+]i were measured using fluo-4, a fluorescent calcium sensitive dye and laser scanning confocal microscopy. Sevoflurane induced an increase on [Ca2+]i from SN56 cells. The sevoflurane-induced increase on [Ca2+]i remained even when the cells were perfused with medium lacking extracellular calcium. However, this effect was abolished by BAPTA-AM, a chelator of intracellular calcium, suggesting the involvement of intracellular Ca2+ stores. Using cyclopiazonic acid, an inhibitor of sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase, we investigated whether the depletion of intracellular Ca2+ stores interfered with the effect of sevoflurane. In the presence of this agent, sevoflurane caused a small but not significant rise on [Ca2+]i of the SN56 cells. Dantrolene, an inhibitor of ryanodine-sensitive calcium stores did not modify the sevoflurane increase on [Ca2+]i. Carbachol, a drug that releases Ca2+ from the IP3 pool, abolished the effect of sevoflurane. In addition, xestospongin D, a cell-permeant IP3 receptor antagonist, decreased significantly the sevoflurane increase on [Ca2+]i. Our data suggest that the sevoflurane-induced increase on [Ca2+]i from SN56 cells occurs through the release of calcium from IP3-sensitive calcium stores.
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PMID:The effect of sevoflurane on intracellular calcium concentration from cholinergic cells. 1653 63

Ryanodine receptors (RyRs) are high conductance intracellular cation channels that release calcium ions from stores such as the endoplasmic reticulum and sarcoplasmic reticulum. Although RyRs are expressed in many cell types, their roles have only been extensively characterised in tissues in which they are abundant: RyR1 is essential for excitation-contraction coupling in skeletal muscle; whereas RyR2 is required for the analogous signal transduction pathway in heart. Defects in RyR1 cause malignant hyperthermia and a spectrum of myopathies in skeletal muscle; whereas RyR2 dysregulation can result in fatal cardiac arrhythmias and is involved in heart failure. Altered RyR gating has been implicated in a range of other diseases, including epilepsy, neurodegeneration, pain and cancer. RyRs interact with a range of toxic substances, providing insights into their functional and structural properties. Consequently, these channel complexes represent potential therapeutic targets for treatment of numerous diseases. Furthermore, strategies for combating multicellular parasites and agricultural pests could exploit pharmacological differences between their RyRs and those of vertebrates. However, available pharmacological tools for manipulation of RyR gating are generally unsuitable for clinical, veterinary or agricultural use, owing to their lack of selectivity, inappropriate solubility in the aqueous or lipid environment, or generation of side-effects. The expression, subcellular distribution and gating of RyRs is modified by a wide variety of cellular proteins, some of which are expressed in a developmentally or tissue-restricted manner. This commentary examines the possibility of manipulating the expression and function of such proteins in order develop new drugs acting on RyR channel complexes.
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PMID:Ryanodine receptor calcium channels and their partners as drug targets. 2009 79

Calcium, as a second messenger, has an important role in a variety of cellular functions. However, disruption of intracellular calcium homeostasis leads to cytotoxicity and cell death. Excessive calcium release from intracellular stores, via the calcium channel ryanodine receptor, contributes to cell damage. Dysfunction of calcium homeostasis is established in tissue culture and animal models of ischemia, hypoxia, seizure, trauma, anesthesia, and neurodegenerative diseases. Dantrolene, the primary drug to treat malignant hyperthermia, is a ryanodine receptor antagonist. Dantrolene inhibits abnormal calcium release from the sarco-endoplasmic reticulum, which is the primary intracellular calcium store. Dantrolene has been investigated widely for its possible cytoprotective effects against cell damage in different tissue culture or animal models of diseases involving cytotoxicity induced by disruption of intracellular calcium homeostasis in pathogenesis. In this review, we summarize the role of the disruption of intracellular calcium homeostasis on cell death, the pharmacologic and pharmacokinetic features of dantrolene, and the cytoprotective effects and potential application of dantrolene for the inhibition of cell damage in a wide variety of models of stress and disease.
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PMID:The cytoprotective effects of dantrolene: a ryanodine receptor antagonist. 2086 18

Ryanodine receptors (RyRs) are located in the sarcoplasmic/endoplasmic reticulum membrane and are responsible for the release of Ca(2+) from intracellular stores during excitation-contraction coupling in both cardiac and skeletal muscle. RyRs are the largest known ion channels (> 2MDa) and exist as three mammalian isoforms (RyR 1-3), all of which are homotetrameric proteins that interact with and are regulated by phosphorylation, redox modifications, and a variety of small proteins and ions. Most RyR channel modulators interact with the large cytoplasmic domain whereas the carboxy-terminal portion of the protein forms the ion-conducting pore. Mutations in RyR2 are associated with human disorders such as catecholaminergic polymorphic ventricular tachycardia whereas mutations in RyR1 underlie diseases such as central core disease and malignant hyperthermia. This chapter examines the current concepts of the structure, function and regulation of RyRs and assesses the current state of understanding of their roles in associated disorders.
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PMID:Ryanodine receptors: structure, expression, molecular details, and function in calcium release. 2096 76

Suxamethonium is the only depolarising neuromuscular blocking agent, which is still being widely used during general anaesthesia. Some of its unique properties rank suxamethonium as an ideal neuromuscular blocking agent i.e. the fast onset of muscle paralysis and spontaneous neuromuscular block reversal. However, the agent may trigger malignant hyperthermia, hyperkaliaemia, severe bradycardia and other complications, which have to be considered. Due to differences in postsynaptic nicotine receptor structure and functional insufficiency of the neuromuscular junction, paediatric patients when compared to adults, are more sensitive to potential side effects when suxamethonium is administered. Malignant hyperthermia is an important risk factor. Ryanidine receptors located in the sarcoplasmic/endoplasmic reticulum membrane are responsible for the release of Ca2+ from intracellular stores and trigger this complication.The risk of hyprethermia increases in children when some neurologic and muscle diseases coexist. Nowadays, in rapid sequence induction of anaesthesia, suxamethonium may be replaced with rocuronium - a non-depolarising muscle relaxant which provides the intubating conditions similar to suxamethonium. The rocuronium-induced neuromuscular blockade, which lasts longer than blockade following suxamethonium, is reversed with sugammadex - a new selective relaxant binding agent. Despite new agents and methods, suxamethonium still remains the drug of choice for muscle relaxation for intubation in children.
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PMID:[Is suxamethonium still useful for paediatric anaesthesia?]. 2201 24

Ryanodine receptors (RyRs) are large ion channels that are responsible for the release of Ca(2+) from the sarcoplasmic/endoplasmic reticulum. Calmodulin (CaM) is a Ca(2+) binding protein that can affect the channel open probability at both high and low Ca(2+) concentrations, shifting the Ca(2+) dependencies of channel opening in an isoform-specific manner. Here we analyze the binding of CaM and its individual domains to three different RyR regions using isothermal titration calorimetry. We compared binding to skeletal muscle (RyR1) and cardiac (RyR2) isoforms, under both Ca(2+)-loaded and Ca(2+)-free conditions. CaM can bind all three regions in both isoforms, but the binding modes differ appreciably in two segments. The results highlight a Ca(2+)/CaM and apoCaM binding site in the C-terminal fifth of the channel. This binding site is the target for malignant hyperthermia and central core disease mutations in RyR1, which affect the energetics and mode of CaM binding.
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PMID:Lobe-specific calmodulin binding to different ryanodine receptor isoforms. 2444 42

Malignant hyperthermia (MH) is a pharmacogenetic disorder that manifests in susceptible individuals exposed to volatile anaesthetics. Over 400 variants in the ryanodine receptor 1 (RYR1) have been reported but relatively few have been definitively associated with susceptibility to MH. This is largely due to the technical challenges of demonstrating abnormal Ca(2+) release from the sarcoplasmic reticulum. This study focuses on the R2452W variant and its functional characterisation with the aim of classifying this variant as MH causative. HEK293 cells were transiently transfected with full-length human wildtype or R2452W mutant RYR1 cDNA. In addition, B-lymphoblastoid cells from blood and myoblasts propagated from in vitro contracture tests were extracted from patients positive for the R2452W variant. All cell lines generated were loaded with the ratiometric dye Fura-2 AM, stimulated with the RYR1-specific agonist 4-chloro-m-cresol and Ca(2+) release from the sarcoplasmic/endoplasmic reticulum was monitored by fluorescence emission. All cells expressing the RYR1 R2452W variant show a significantly higher Ca(2+) release in response to the agonist, 4-chloro-m-cresol, compared to cells expressing RYR1 WT. These results indicate that the R2452W variant results in a hypersensitive ryanodine receptor 1 and suggest that the R2452W variant in the ryanodine receptor 1 is likely to be causative of MH.
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PMID:Functional characterisation of the R2452W ryanodine receptor variant associated with malignant hyperthermia susceptibility. 2508 7

Alzheimer disease (AD) is a fatal progressive disease and the most common form of dementia without effective treatments. Previous studies support that the disruption of endoplasmic reticulum Ca through overactivation of ryanodine receptors plays an important role in the pathogenesis of AD. Normalization of intracellular Ca homeostasis could be an effective strategy for AD therapies. Dantrolene, an antagonist of ryanodine receptors and an FDA-approved drug for clinical treatment of malignant hyperthermia and muscle spasms, exhibits neuroprotective effects in multiple models of neurodegenerative disorders. Recent preclinical studies consistently support the therapeutic effects of dantrolene in various types of AD animal models and were summarized in the current review.
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PMID:Dantrolene, a treatment for Alzheimer disease? 2555 62

Interaction between the endoplasmic reticulum (ER)-located stromal interaction molecue1 (STIM1) and the plasma membrane-located Ca(2+) channel subunit, Orai1, underlies store-operated Ca(2+) entry (SOCE). Calsequestrin1 (CSQ1), a sarcoplasmic reticulum Ca(2+) buffering protein, inhibits SOCE, but the mechanism of action is unknown. We identified an interaction between CSQ1 and STIM1 in HEK293 cells. An increase in monomeric CSQ1 induced by depleted Ca(2+) stores, or trifluoperazine (TFP), a blocker of CSQ folding and aggregation, enhanced the CSQ1-STIM1 interaction. In cells with Ca(2+) stores depleted, TFP further increased CSQ1 monomerization and CSQ1-STIM1 interaction, but reduced the association of STIM1 with Orai1 and SOCE. Over-expression of CSQ1 or a C-terminal (amino acid 388-396) deletion mutant significantly promoted the association of CSQ1 with STIM1, but suppressed both STIM1-Orai1 interaction and SOCE, while over-expression of the C-terminal (amino acid 362-396) deletion mutant had no effect. The physical interaction between low polymeric forms of CSQ1 and STIM1 likely acts by interfering with STIM1 oligimerization and inhibits STIM1-Orai1 interaction, providing a brake to SOCE under physiological conditions. This novel regulatory mechanism for SOCE may also contribute to the pathological Ca(2+) overload in calsequestrin deficient diseases, such as malignant hyperthermia and ventricular tachycardia.
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PMID:Retrograde regulation of STIM1-Orai1 interaction and store-operated Ca2+ entry by calsequestrin. 2608 26


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