Ca-induced Ca release in malignant hyperthermia-susceptible pig skeletal muscle

Ohta, Toshio; Endo, Makoto; Nakano, Tomoko; Morohoshi, Yasuo; Wanikawa, K.; Ohga, Akira

doi:10.1152/ajpcell.1989.256.2.c358

Cited by 74 publications

(45 citation statements)

References 13 publications

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“…In agreement with previous reports (7,12,13,45,46), we found that the extent of dantrolene inhibition of DP4-induced RyR1 channel activation, as determined by both [ 3 H]ryanodine binding and SR Ca 2ϩ release, varies with the temperature, i.e. significant inhibition was observed at 37°C, with only negligible inhibition at 22°C.…”

Section: Table III Inhibition Of Sr Ca 2ϩ Release By Dantrolene: Effesupporting

confidence: 93%

“…CaM alone (1 M) increased the specific activity of [ 3 H]ryanodine binding to the SR at 22°C, but dantrolene was now able to significantly suppress radioligand binding (ϳ35%) (Table II). When we carried out the same type of experiments at 37°C, dantrolene produced equivalently significant inhibition of [ 3 H]ryanodine binding (ϳ59%) in the presence or absence of CaM, in agreement with previous reports (7,12,13,45). These results suggest that higher temperature and CaM have similar effects on the extent of dantrolene inhibition of DP4-induced activation of RyR Ca 2ϩ channels.…”

Section: Inhibition Of Skeletal Muscle Sr Ryanodine Binding and Ca 2ϩsupporting

confidence: 91%

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Dantrolene Stabilizes Domain Interactions within the Ryanodine Receptor

Kobayashi

Bannister

Gangopadhyay

et al. 2005

Journal of Biological Chemistry

119

111

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Interdomain interactions between N-terminal and central domains serving as a "domain switch" are believed to be essential to the functional regulation of the skeletal muscle ryanodine receptor-1 Ca 2؉ channel. Mutational destabilization of the domain switch in malignant hyperthermia (MH), a genetic sensitivity to volatile anesthetics, causes functional instability of the channel. Dantrolene, a drug used to treat MH, binds to a region within this proposed domain switch. To explore its mechanism of action, the effect of dantrolene on MH-like channel activation by the synthetic domain peptide DP4 or anti-DP4 antibody was examined. A fluorescence probe, methylcoumarin acetate, was covalently attached to the domain switch using DP4 as a delivery vehicle. The magnitude of domain unzipping was determined from the accessibility of methylcoumarin acetate to a macromolecular fluorescence quencher. The SternVolmer quenching constant (K Q ) increased with the addition of DP4 or anti-DP4 antibody. This increase was reversed by dantrolene at both 37 and 22°C and was unaffected by calmodulin. [ 3 H]Ryanodine binding to the sarcoplasmic reticulum and activation of sarcoplasmic reticulum Ca 2؉ release, both measures of channel activation, were enhanced by DP4. These activities were inhibited by dantrolene at 37°C, yet required the presence of calmodulin at 22°C. These results suggest that the mechanism of action of dantrolene involves stabilization of domain-domain interactions within the domain switch, preventing domain unzipping-induced channel dysfunction. We suggest that temperature and calmodulin primarily affect the coupling between the domain switch and the downstream mechanism of regulation of Ca 2؉ channel opening rather than the domain switch itself.Dantrolene (hydrated 1-(((5-(4-nitrophenyl)-2-furanyl)methylene)amino)-2,4-imidazolidinedione sodium salt) is an intracellularly acting skeletal muscle relaxant used for the treatment of malignant hyperthermia (MH). 1 MH is a potentially deadly, pharmacogenetically mediated, hypermetabolic response to volatile anesthetics that results from unregulated intramyoplasmic Ca 2ϩ release (1). The drug is known to inhibit excitation-contraction coupling of skeletal muscle (2) by suppressing depolarization-induced sarcoplasmic reticulum (SR) Ca 2ϩ release in normal and MH-susceptible skeletal muscle without affecting voltage sensor activation (3). In MH, the voltage dependence of contractile activation is shifted to lower voltages (4), whereas in the presence of clinical concentrations of dantrolene, i.e. 10 M (5), the voltage dependence of contractile activation is shifted to higher voltages (6, 7). Normalization of the voltage dependence of contractile activation may therefore be one of the important components of the therapeutic action of dantrolene. Dantrolene also confers a normal Mg 2ϩ sensitivity to MH-susceptible muscle fibers, which would otherwise show a considerably reduced sensitivity to the normal inhibitory action of myoplasmic Mg 2ϩ on the SR Ca 2ϩ release mechanism (...

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Section: Table III Inhibition Of Sr Ca 2ϩ Release By Dantrolene: Effesupporting

confidence: 93%

Section: Inhibition Of Skeletal Muscle Sr Ryanodine Binding and Ca 2ϩsupporting

confidence: 91%

Dantrolene Stabilizes Domain Interactions within the Ryanodine Receptor

Kobayashi

Bannister

Gangopadhyay

et al. 2005

Journal of Biological Chemistry

119

111

View full text Add to dashboard Cite

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“…As a positive control, we also introduced an Arg615Cys (R615C) mutation, which is known as the causal mutation in porcine stress syndrome, an animal model of MH (24). Indeed, significant acceleration of the CICR has been detected in muscle samples from MH pigs (25). RyR1 cDNAs carrying one of these mutations were coexpressed in CHO cells with EGFP using a bidirectional expression vector (26).…”

Section: Expression and Functional Analysis Of The Two Novel Ryr1 Mutmentioning

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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“…Indeed the patient took cefpodoxime proxetil and indomethacin but these agents have not been documented to cause malignant hyperthermia or neuroleptic malignant syndrome. In patients with malignant hyperthermia, the calcium release rate in the sarcoplasmic reticulum was demonstrated to be abnormally enhanced by the stimulation of calcium, with the use of skinned fiber preparations (2,5). Therefore the possibility was tested by this method using the present patient's muscle specimen.…”

Section: Discussionmentioning

confidence: 97%

“…Using this, the calcium release rate in the sarcoplasmic reticulum was measured (2,5). The calcium release rate was measured with application of5 different concentrations of calcium: 0, 0.3, 1.0, 3.0 and 10 \\M.…”

Section: Blood Purificationmentioning

confidence: 99%

Massive Rhabdomyolysis Associated with Influenza A Infection.

Wakabayashi¹,

Nakano²,

Kikuno³

et al. 1994

Intern. Med.

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A 20-year-old male with massive rhabdomyolysis associated with a high fever and acute renal failure is reported. Influenza Ainfection was confirmed serologically. Myoglobinkinetics was studied in this case. Blood myoglobin fell exponentially independent of renal function or therapeutic modality such as hemodialysis/filtration, once myoglobin release into the circulation ceased. The finding suggested that catabolic steps ofmyoglobin take place extrarenally in patients with massive rhabdomyolysis and acute renal failure. (Internal Medicine 33: 450-453, 1994)

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Ca-induced Ca release in malignant hyperthermia-susceptible pig skeletal muscle

Cited by 74 publications

References 13 publications

Dantrolene Stabilizes Domain Interactions within the Ryanodine Receptor

Dantrolene Stabilizes Domain Interactions within the Ryanodine Receptor

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

Massive Rhabdomyolysis Associated with Influenza A Infection.

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