scholarly journals Therapeutic effects of novel type 1 ryanodine receptor inhibitor on malignant hyperthermia

2021 ◽  
Vol 154 (9) ◽  
Author(s):  
Toshiko Yamazawa
Keyword(s):  
Skeletal Muscle ◽  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Half Life ◽  
Water Solubility ◽  
Heat Stroke ◽  
Therapeutic Effects ◽  
Ryr1 Gene ◽  
Plasma Half Life

Ca2+-induced Ca2+ release (CICR) is mediated by ryanodine receptors, a Ca2+ release channel in the sarcoplasmic/endoplasmic reticulum (SR/ER), and plays an important role in various tissues. Type 1 ryanodine receptor (RYR1) plays a key role during excitation–contraction coupling of skeletal muscle. Mutations in RYR1 overactivate the channel to cause malignant hyperthermia (MH). MH is a serious complication characterized by skeletal muscle rigidity and elevated body temperature in response to commonly used inhalational anesthetics. Thus far, >300 mutations in the RYR1 gene have been reported in patients with MH. Some heat stroke triggered by exercise or environmental heat stress is also related to MH mutations in the RYR1 gene. The only drug approved for ameliorating the symptoms of MH is dantrolene, which has been first developed in the 1960s as a muscle relaxant. However, dantrolene has several disadvantages for clinical use: poor water solubility, which makes rapid preparation difficult in emergency situations, and long plasma half-life, which causes long-lasting side effects such as muscle weakness. Here, we show that a novel RYR1-selective inhibitor, 6,7-(methylenedioxy)-1-octyl-4-quinolone-3-carboxylic acid (compound 1 [Cpd1]), effectively rescues MH and heat stroke in new mouse model (RYR1-p.R2509C) relevant to MH. Cpd1 has great advantages of higher water solubility and shorter plasma half-life compared with dantrolene. Our data suggest that Cpd1 has the potential to be a promising new candidate for effective treatment of patients carrying RYR1 mutations. Finally, we have recently identified that heat directly activates RYR1, which induces Ca2+ release from intracellular stores. Our results provide direct evidence that heat induces Ca2+ release (HICR) from the SR through the mutants rather than wild type RYR1, causing an immediate rise in the cytosolic Ca2+ concentration.

scholarly journals A novel saline-soluble, rapidly-metabolized RyR1 inhibitor rescues volatile anesthesia-induced death and environmental heat stroke in a mouse model relevant to malignant hyperthermia

2020 ◽  
Author(s):  
Toshiko Yamazawa ◽  
Takuya Kobayashi ◽  
Nagomi Kurebayashi ◽  
Masato Konishi ◽  
Satoru Noguchi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Malignant Hyperthermia ◽  
Water Solubility ◽  
Heat Stroke ◽  
Release Channel ◽  
Volatile Anesthesia ◽  
Intracellular Ca ◽  
Rapid Clearance

AbstractMutations in the type 1 ryanodine receptor (RyR1), a Ca2+ release channel in skeletal muscle, hyperactivate the channel to cause malignant hyperthermia (MH) and are implicated in severe heat stroke. Dantrolene, the only approved drug for MH, has the disadvantages of having very poor water solubility and long plasma half-life. We show here that a novel RyR1-selective inhibitor, 6,7-(methylenedioxy)-1-octyl-4-quinolone-3-carboxylic acid (Compound 1), effectively rescues MH and heat stroke in several mouse models relevant to MH. Compound 1 reduced resting intracellular Ca2+, inhibited halothane-induced Ca2+ release, suppressed caffeine-induced contracture in skeletal muscle, reduced sarcolemmal cation influx, and prevented or reversed the fulminant MH crisis by isoflurane anesthesia and heat stroke by environmental heat stress. Notably, Compound 1 has great advantages of better water solubility and rapid clearance in vivo over dantrolene. Compound 1 has the potential to be a promising new candidate for effective treatment of patients carrying RyR1 mutations.

scholarly journals Scanning for Mutations of the Ryanodine Receptor (RYR1) Gene by Denaturing HPLC: Detection of Three Novel Malignant Hyperthermia Alleles

2003 ◽  
Vol 49 (5) ◽  
pp. 761-768 ◽  
Author(s):  
Angela Tammaro ◽  
Adele Bracco ◽  
Santolo Cozzolino ◽  
Maria Esposito ◽  
Antonietta Di Martino ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Sudden Increase ◽  
Gene Encoding ◽  
In Vitro Contracture Test ◽  
Ryr1 Gene ◽  
Molecular Tests ◽  
Anesthetic Agents

Abstract Background: Malignant hyperthermia (MH) is a fatal autosomal dominant pharmacogenetic disorder characterized by skeletal muscle hypertonicity that causes a sudden increase in body temperature after exposure to common anesthetic agents. The disease is genetically heterogeneous, with mutations in the gene encoding the skeletal muscle ryanodine receptor (RYR1) at 19q13.1 accounting for up to 80% of the cases. To date, at least 42 RYR1 mutations have been described that cause MH and/or central core disease. Because the RYR1 gene is huge, containing 106 exons, molecular tests have focused on the regions that are more frequently mutated. Thus the causative defect has been identified in only a fraction of families as linked to chromosome 19q, whereas in others it remains undetected. Methods: We used denaturing HPLC (DHPLC) to analyze the RYR1 gene. We set up conditions to scan the 27 exons to identify both known and unknown mutations in critical regions of the protein. For each exon, we analyzed members from 52 families with positive in vitro contracture test results, but without preliminary selection by linkage analysis. Results: We identified seven different mutations in 11 MH families. Among them, three were novel MH alleles: Arg44Cys, Arg533Cys, and Val2117Leu. Conclusion: Because of its sensitivity and speed, DHPLC could be the method of choice for the detection of unknown mutations in the RYR1 gene.

Treatment of Normal Skeletal Muscle with FK506 or Rapamycin Results in Halothane-induced Muscle Contracture

1998 ◽  
Vol 89 (3) ◽  
pp. 693-698. ◽  
Author(s):  
Richard L. Brooksbank ◽  
Margaret E. Badenhorts ◽  
Hyam Isaacs ◽  
Nerina Savage
Keyword(s):  
Carbon Dioxide ◽  
Skeletal Muscle ◽  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Human Skeletal Muscle ◽  
Receptor Type ◽  
Muscle Strip ◽  
Healthy Human ◽  
Healthy Persons

Background FKBP12 is a protein that is closely associated with the ryanodine receptor type 1 of skeletal muscle and modulates Ca2+ release by the channel. The immunosuppressants FK506 and rapamycin both bind to FKBP12 and in turn dissociate the protein from the ryanodine receptor. By treating healthy human skeletal muscle strips with FK506 or rapamycin and then subjecting the strips to the caffeine-halothane contracture test, this study determined that FK506 and rapamycin alter the sensitivity of the muscle strip to halothane, caffeine, or both. Methods Skeletal muscle strips from 10 healthy persons were incubated in Krebs medium equilibrated with a 95% oxygen and 5% carbon dioxide mixture, which contained either 12 microM FK506 (n = 8) or 12 microM rapamycin (n = 6), for 15 min at 37 degrees C. The strips were subjected to the caffeine-halothane contracture test for malignant hyperthermia according to the European Malignant Hyperthermia Group protocol. Results Treatment of normal skeletal muscle strips with FK506 and rapamycin resulted in halothane-induced contractures of 0.44+/-0.16 g and 0.6+/-0.49 g, respectively, at 2% halothane. Conclusions The results obtained show that pre-exposure of healthy skeletal muscle strips to either FK506 or rapamycin is sufficient to give rise to halothane-induced contractures. This is most likely caused by destabilization of Ca2+ release by the ryanodine receptor as a result of the dissociation of FKBP12. This finding suggests that a mutation in FKBP12 or changes in its capacity to bind to the ryanodine receptor could alter the halothane sensitivity of the skeletal muscle ryanodine receptor and thereby predispose the person to malignant hyperthermia.

scholarly journals A novel RyR1-selective inhibitor prevents and rescues sudden death in mouse models of malignant hyperthermia and heat stroke

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Toshiko Yamazawa ◽  
Takuya Kobayashi ◽  
Nagomi Kurebayashi ◽  
Masato Konishi ◽  
Satoru Noguchi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Malignant Hyperthermia ◽  
Mouse Models ◽  
Water Solubility ◽  
Heat Stroke ◽  
Selective Inhibitor ◽  
Release Channel ◽  
Intracellular Ca ◽  
Rapid Clearance

AbstractMutations in the type 1 ryanodine receptor (RyR1), a Ca2+ release channel in skeletal muscle, hyperactivate the channel to cause malignant hyperthermia (MH) and are implicated in severe heat stroke. Dantrolene, the only approved drug for MH, has the disadvantages of having very poor water solubility and long plasma half-life. We show here that an oxolinic acid-derivative RyR1-selective inhibitor, 6,7-(methylenedioxy)-1-octyl-4-quinolone-3-carboxylic acid (Compound 1, Cpd1), effectively prevents and treats MH and heat stroke in several mouse models relevant to MH. Cpd1 reduces resting intracellular Ca2+, inhibits halothane- and isoflurane-induced Ca2+ release, suppresses caffeine-induced contracture in skeletal muscle, reduces sarcolemmal cation influx, and prevents or reverses the fulminant MH crisis induced by isoflurane anesthesia and rescues animals from heat stroke caused by environmental heat stress. Notably, Cpd1 has great advantages of better water solubility and rapid clearance in vivo over dantrolene. Cpd1 has the potential to be a promising candidate for effective treatment of patients carrying RyR1 mutations.

Postulated role of interdomain interactions within the type 1 ryanodine receptor in the low gain of Ca2+-induced Ca2+ release activity of mammalian skeletal muscle sarcoplasmic reticulum

2005 ◽  
Vol 288 (6) ◽  
pp. C1222-C1230 ◽  
Author(s):  
Takashi Murayama ◽  
Toshiharu Oba ◽  
Shigeki Kobayashi ◽  
Noriaki Ikemoto ◽  
Yasuo Ogawa
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Single Channel ◽  
Common Mechanism ◽  
Mammalian Skeletal Muscle ◽  
Selective Stabilization ◽  
Interdomain Interactions

Ryanodine receptor (RyR) type 1 (RyR1) exhibits a markedly lower gain of Ca2+-induced Ca2+ release (CICR) activity than RyR type 3 (RyR3) in the sarcoplasmic reticulum (SR) of mammalian skeletal muscle (selective stabilization of the RyR1 channel), and this reduction in the gain is largely eliminated using 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid (CHAPS). We have investigated whether the hypothesized interdomain interactions within RyR1 are involved in the selective stabilization of the channel using [3H]ryanodine binding, single-channel recordings, and Ca2+ release from the SR vesicles. Like CHAPS, domain peptide 4 (DP4, a synthetic peptide corresponding to the Leu2442-Pro2477 region of RyR1), which seems to destabilize the interdomain interactions, markedly stimulated RyR1 but not RyR3. Their activating effects were saturable and nonadditive. Dantrolene, a potent inhibitor of RyR1 used to treat malignant hyperthermia, reversed the effects of DP4 or CHAPS in an identical manner. These findings indicate that RyR1 is activated by DP4 and CHAPS through a common mechanism that is probably mediated by the interdomain interactions. DP4 greatly increased [3H]ryanodine binding to RyR1 with only minor alterations in the sensitivity to endogenous CICR modulators (Ca2+, Mg2+, and adenine nucleotide). However, DP4 sensitized RyR1 four- to six-fold to caffeine in the caffeine-induced Ca2+ release. Thus the gain of CICR activity critically determines the magnitude and threshold of Ca2+ release by drugs such as caffeine. These findings suggest that the low CICR gain of RyR1 is important in normal Ca2+ handling in skeletal muscle and that perturbation of this state may result in muscle diseases such as malignant hyperthermia.

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