Therapeutic effects of novel type1 ryanodine receptor inhibitor on skeletal muscle diseases

2022 ◽  
Vol 157 (1) ◽  
pp. 15-22
Author(s):  
Toshiko Yamazawa ◽  
Takuya Kobayashi ◽  
Nagomi Kurebayashi ◽  
Takashi Murayama
Keyword(s):  
Skeletal Muscle ◽  
Ryanodine Receptor ◽  
Therapeutic Effects ◽  
Muscle Diseases ◽  
Receptor Inhibitor

scholarly journals Malignant hyperthermia-associated mutations in the S2-S3 cytoplasmic loop of type 1 ryanodine receptor calcium channel impair calcium-dependent inactivation

2016 ◽  
Vol 311 (5) ◽  
pp. C749-C757 ◽  
Author(s):  
Angela C. Gomez ◽  
Timothy W. Holford ◽  
Naohiro Yamaguchi
Keyword(s):  
Skeletal Muscle ◽  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Wild Type ◽  
Cytoplasmic Loop ◽  
Muscle Diseases ◽  
Calcium Dependent ◽  
Transmembrane Segments ◽  
Channel Regulation ◽  
Dependent Inactivation

Channel activities of skeletal muscle ryanodine receptor (RyR1) are activated by micromolar Ca2+ and inactivated by higher (∼1 mM) Ca2+. To gain insight into a mechanism underlying Ca2+-dependent inactivation of RyR1 and its relationship with skeletal muscle diseases, we constructed nine recombinant RyR1 mutants carrying malignant hyperthermia or centronuclear myopathy-associated mutations and determined RyR1 channel activities by [3H]ryanodine binding assay. These mutations are localized in or near the RyR1 domains which are responsible for Ca2+-dependent inactivation of RyR1. Four RyR1 mutations (F4732D, G4733E, R4736W, and R4736Q) in the cytoplasmic loop between the S2 and S3 transmembrane segments (S2–S3 loop) greatly reduced Ca2+-dependent channel inactivation. Activities of these mutant channels were suppressed at 10–100 μM Ca2+, and the suppressions were relieved by 1 mM Mg2+. The Ca2+- and Mg2+-dependent regulation of S2–S3 loop RyR1 mutants are similar to those of the cardiac isoform of RyR (RyR2) rather than wild-type RyR1. Two mutations (T4825I and H4832Y) in the S4–S5 cytoplasmic loop increased Ca2+ affinities for channel activation and decreased Ca2+ affinities for inactivation, but impairment of Ca2+-dependent inactivation was not as prominent as those of S2–S3 loop mutants. Three mutations (T4082M, S4113L, and N4120Y) in the EF-hand domain showed essentially the same Ca2+-dependent channel regulation as that of wild-type RyR1. The results suggest that nine RyR1 mutants associated with skeletal muscle diseases were differently regulated by Ca2+ and Mg2+. Four malignant hyperthermia-associated RyR1 mutations in the S2–S3 loop conferred RyR2-type Ca2+- and Mg2+-dependent channel regulation.

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.

Tropomyosin mutations responsible for muscle weakness in inherited skeletal muscle diseases

2008 ◽  
pp. 20-21
Author(s):  
Julien Ochala ◽  
Anders Oldfors ◽  
Lars Larsson
Keyword(s):  
Skeletal Muscle ◽  
Muscle Weakness ◽  
Muscle Diseases

Primary structure and expression from complementary DNA of skeletal muscle ryanodine receptor

Nature ◽  
1989 ◽  
Vol 339 (6224) ◽  
pp. 439-445 ◽  
Author(s):  
Hiroshi Takeshima ◽  
Seiichiro Nishimura ◽  
Takeshi Matsumoto ◽  
Hiroyuki Ishida ◽  
Kenji Kangawa ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Ryanodine Receptor ◽  
Primary Structure ◽  
Complementary Dna

Reciprocal dihydropyridine and ryanodine receptor interactions in skeletal muscle activation

2011 ◽  
Vol 32 (3) ◽  
pp. 171-202 ◽  
Author(s):  
Christopher L.-H. Huang ◽  
Thomas H. Pedersen ◽  
James A. Fraser
Keyword(s):  
Skeletal Muscle ◽  
Ryanodine Receptor ◽  
Muscle Activation ◽  
Receptor Interactions
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