Caffeine and Halothane Sensitivity of Intracellular Ca2+ Release Is Altered by 15 Calcium Release Channel (Ryanodine Receptor) Mutations Associated with Malignant Hyperthermia and/or Central Core Disease

Tong, Jiefei; Oyamada, Hideto; Demaurex, Nicolas; Grinstein, Sergio; McCarthy, Tommie V.; MacLennan, David H.

doi:10.1074/jbc.272.42.26332

Cited by 242 publications

(242 citation statements)

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“…Each of 15 MH and CCD channels with mutations in MH regions 1 and 2 were found to be more sensitive to the triggering action of halothane and caffeine than wild-type, accounting for the ability of halothane to trigger an MH response in susceptible individuals, but not in normal individuals [55]. Both MH and CCD channels with mutations in these two regions were found to be more permeable than wildtype channels.…”

Section: I F F E R E N T I a T I O N B E T W E E N M H A N D C C D mentioning

confidence: 94%

Ca²⁺ signalling and muscle disease

MacLennan

2000

European Journal of Biochemistry

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Transient elevations of intracellular Ca2+ play a signalling role in such complex cellular functions as contraction, secretion, fertilization, proliferation, metabolism, heartbeat and memory. However, prolonged elevation of Ca2+ above about 10 µm is deleterious to a cell and can activate apoptosis. In muscle, there is a narrow window of Ca2+ dysregulation in which abnormalities in Ca2+ regulatory proteins can lead to disease, rather than apoptosis. Key proteins in the regulation of muscle Ca2+ are the voltage‐dependent, dihydropyridine‐sensitive, l‐type Ca2+ channels located in the transverse tubule and Ca2+ release channels in the junctional terminal cisternae of the sarcoplasmic reticulum. Abnormalities in these proteins play a key role in malignant hyperthermia (MH), a toxic response to anesthetics, and in central core disease (CCD), a muscle myopathy. Sarco(endo)plasmic reticulum Ca2+ ATPases (SERCAs) return sarcoplasmic Ca2+ to the lumen of the sarcoplasmic reticulum. Loss of SERCA1a Ca2+ pump function is one cause of exercise‐induced impairment of the relaxation of skeletal muscle, in Brody disease. Phospholamban expressed in cardiac muscle and sarcolipin expressed in skeletal muscle regulate SERCA activity. Studies with knockout and transgenic mice show that gain of inhibitory function of phospholamban alters cardiac contractility and could be a causal feature in some cardiomyopathies. Calsequestrin, calreticulin, and a series of other acidic, lumenal, Ca2+ binding proteins provide a buffer for Ca2+ stored in the sarcoplasmic reticulum. Overexpression of cardiac calsequestrin leads to cardiomyopathy and ablation of calreticulin alters cardiac development.

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Section: I F F E R E N T I a T I O N B E T W E E N M H A N D C C D mentioning

confidence: 94%

Ca²⁺ signalling and muscle disease

MacLennan

2000

European Journal of Biochemistry

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“…Those mutations associated with weaker contractures may therefore be expected to show higher discordance rates than those associated with more severe contracture phenotypes. All three mutations have been shown to be associated with weaker contractures compared to 487C4T, 6487C4T, 6488G4A and 7304G4A by analysis of channel mutants in vitro 18 and by comparative analysis of IVCT data in mutation carriers. 36,37 With over 500 individuals investigated for RYR1 mutations currently used in genetic diagnosis, this represents the most comprehensive evaluation of mutation prevalence and genotype/phenotype concordance data.…”

Section: Discussionmentioning

confidence: 99%

“…17 Genetic testing guidelines have been recently published by the EMHG to enable DNA diagnosis of MH in supplementation to the IVCT method of patient screening in MH families. In summary, genetic testing using certain mutations in the RYR1 gene demonstrated to be 'causative' of MH through in vitro biochemical assays, 18,19 or through linkage analysis with markers flanking the RYR1 locus is now feasible. Individuals carrying a 'causative' mutation or high-risk susceptibility haplotype are considered at risk of developing MH independent of IVCT diagnoses.…”

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confidence: 99%

Recent advances in the diagnosis of malignant hyperthermia susceptibility: How confident can we be of genetic testing?

Robinson

Anetseder

Brancadoro³

et al. 2003

Eur J Hum Genet

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Malignant hyperthermia (MH) is a condition that manifests in susceptible individuals only on exposure to certain anaesthetic agents. Although genetically heterogeneous, mutations in the RYR1 gene (19q13.1) are associated with the majority of reported MH cases. Guidelines for the genetic diagnosis for MH susceptibility have recently been introduced by the European MH Group (EMHG). These are designed to supplement the muscle biopsy testing procedure, the in vitro contracture test (IVCT), which has been the only means of patient screening for the last 30 years and which remains the method for definitive diagnosis in suspected probands. Discordance observed in some families between IVCT phenotype and susceptibility locus genotype could limit the confidence in genetic diagnosis. We have therefore assessed the prevalence of 15 RYR1 mutations currently used in the genetic diagnosis of MH in a sample of over 500 unrelated European MH susceptible individuals and have recorded the frequency of RYR1 genotype/IVCT phenotype discordance. RYR1 mutations were detected in up to B30% of families investigated. Phenotype/genotype discordance in a single individual was observed in 10 out of 196 mutation-positive

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“…The CHO cells were cultured for approximately 48 h after the transfection, and then they were fixed, permeabilized and blocked as previously described (20). Polyclonal antibodies against the D2 region (amino acids 1358 -1413) of rabbit RyR1 (21) and the tetramethylrhodamine isothiocyanate (TRITC)-conjugated anti-rabbit IgG antibodies (Jackson ImmunoResearch Laboratories, West Grove, PA, USA) were used to detect the expressed RyR1 protein in the CHO cells.…”

Section: Immunocytochemistry Of Extrinsic Ryr1mentioning

confidence: 99%

“…Site-directed mutagenesis (19) was carried out in cassettes C2 (Sal I/ Bst BI), C9 (Nde I / Nhe I), C10 (Nhe I /Cla I) or C11 (Cla I/ Hind III) excised from the full-length cDNA of rabbit RYR1 (pBS-RYR1, (20)) using the following mutagenic primers (underlines show the codons for each mutated amino acid. ): 5'-caatggtcgggctgtgtgttcgaaccaa gatctcatcaccg-3' for R615C, 5'-caactgcctcaaggtctccctggtga tcttc-3' for P4667S, and 5'-caatgggaaacacgtggtgatgactg-3' for L4837V.…”

Section: Oligonucleotide-directed Mutagenesismentioning

confidence: 99%

Novel Mutations in C-terminal Channel Region of the Ryanodine Receptor in Malignant Hyperthermia Patients

Oyamada

Oguchi

Saitoh

et al. 2002

Japanese Journal of Pharmacology

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ABSTRACT-Malignant hyperthermia (MH) is a pharmacogenetical complication of general anesthesia resulting from abnormal Ca 2+ -induced Ca 2+ release (CICR) via the type 1 ryanodine receptor (RyR1) in skeletal muscles. In this study, we analyzed the genomic DNAs prepared for determination of all the 106 exons of the RyR1 gene from blood samples donated by two MH patients with extremely high CICR rates in their biopsied skeletal muscles and a clear history of MH incidence. Two novel point mutations were found in the exons 96 and 101 with alterations in the coded amino acids within the C-terminal channel region, i.e., Pro4668 to Ser and Leu4838 to Val. The latter mutation was found in both MH patients. Rabbit RyR1 channels carrying corresponding mutations were expressed in CHO cells for functional assay. It was found that the L to V but not the P to S mutation of the RyR1 resulted in enhanced Ca 2+ release activity. These results indicate that the L4838V mutation is responsible for the MH incidence. The L4838V mutation is unique because it is the mutation first found within a hydrophobic transmembrane segment of the channel region and should provide further information on the function of the RyR1 as well as for genetic diagnosis of MH.Keywords: Calcium, Sarcoplasmic reticulum, Skeletal muscle, Mutation, General anesthesia Malignant hyperthermia (MH) is a serious complication of general anesthesia triggered by commonly used inhalational anesthetics (1 -3). The typical symptoms include a rapid increase in body temperature and induction of a hypermetabolic state with skeletal muscle rigidity. These symptoms, if not immediately reversed, result in death of the patient. The predisposition to MH is inherited as an autosomal dominant trait. The first hint of the nature of the abnormality in MH patients was obtained when Kalow et al. (4) demonstrated that the patients' muscle has a higher sensitivity than normal muscle to the contracture-inducing action of caffeine applied with or without halothane as a potentiator. It has been shown that caffeine or halothane accelerates the Ca 2+ -induced Ca 2+ release (CICR) mechanism in the sarcoplasmic reticulum (SR) of striated muscle (5, 6). Endo et al. (6) demonstrated that both Ca 2+ sensitivity and the maximum rate of CICR in an MH patient were much higher than those in control human muscles. Thus, induction of muscle contracture due to pharmacological enhancement of CICR by inhalational anesthetics in addition to a genetic basis of CICR acceleration was considered to be the primary cause of elevated body temperature in MH episodes. Furthermore, a cluster analysis based on the rates of CICR in 84 patients suspected of having MH objectively classified the patients into three groups, and a strong correlation was identified between the clinical signs of MH during anesthesia and the acceleration of CICR (7).The channel protein responsible for the CICR was isolated through its high-affinity binding of the plant alkaloid ryanodine; hence it is called the ryanodine receptor (RyR). The...

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Caffeine and Halothane Sensitivity of Intracellular Ca2+ Release Is Altered by 15 Calcium Release Channel (Ryanodine Receptor) Mutations Associated with Malignant Hyperthermia and/or Central Core Disease

Cited by 242 publications

References 45 publications

Ca²⁺ signalling and muscle disease

Ca²⁺ signalling and muscle disease

Recent advances in the diagnosis of malignant hyperthermia susceptibility: How confident can we be of genetic testing?

Novel Mutations in C-terminal Channel Region of the Ryanodine Receptor in Malignant Hyperthermia Patients

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Caffeine and Halothane Sensitivity of Intracellular Ca2+ Release Is Altered by 15 Calcium Release Channel (Ryanodine Receptor) Mutations Associated with Malignant Hyperthermia and/or Central Core Disease

Cited by 242 publications

References 45 publications

Ca2+ signalling and muscle disease

Ca2+ signalling and muscle disease

Recent advances in the diagnosis of malignant hyperthermia susceptibility: How confident can we be of genetic testing?

Novel Mutations in C-terminal Channel Region of the Ryanodine Receptor in Malignant Hyperthermia Patients

Contact Info

Product

Resources

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Ca²⁺ signalling and muscle disease

Ca²⁺ signalling and muscle disease