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)

The molecular defect predisposing to the majority of malignant hyperthermia (MH) cases is unknown, although various point mutations in the ryanodine receptor gene (RYR1) have been associated with susceptibility in a small proportion of cases. We report here that one of these, the Arg163Cys substitution, does not cosegregate with MH susceptibility. Comparison of cDNA sequences encoding the skeletal muscle specific components of the dihydropyridine receptor alpha 1 subunit between MH susceptible (MHS) and MH non-susceptible (MHN) patients was made in subjects without the reported MH linked RYR1 mutations. There were no differences within the sequence encoding the II-III loop or the IS3/IS3-IS4 segment, excluding defects in these functional segments of the alpha 1 subunit as frequent causes of MH.
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PMID:Exclusion of defects in the skeletal muscle specific regions of the DHPR alpha 1 subunit as frequent causes of malignant hyperthermia. 859 42

Dantrolene is a drug that suppresses intracellular Ca(2+) release from sarcoplasmic reticulum (SR) in skeletal muscle and is used as a therapeutic agent in individuals susceptible to malignant hyperthermia. Although its precise mechanism of action has not been elucidated, we have identified the N-terminal region (amino acids 1-1400) of the skeletal muscle isoform of the ryanodine receptor (RyR1), the primary Ca(2+) release channel in SR, as a molecular target for dantrolene using the photoaffinity analog [(3)H]azidodantrolene. Here, we demonstrate that heterologously expressed RyR1 retains its capacity to be specifically labeled with [(3)H]azidodantrolene, indicating that muscle specific factors are not required for this ligand-receptor interaction. Synthetic domain peptides of RyR1 previously shown to affect RyR1 function in vitro and in vivo were exploited as potential drug binding site mimics and used in photoaffinity labeling experiments. Only DP1 and DP1-2s, peptides containing the amino acid sequence corresponding to RyR1 residues 590-609, were specifically labeled by [(3)H]azidodantrolene. A monoclonal anti-RyR1 antibody that recognizes RyR1 and its 1400-amino acid N-terminal fragment recognizes DP1 and DP1-2s in both Western blots and immunoprecipitation assays and specifically inhibits [(3)H]azidodantrolene photolabeling of RyR1 and its N-terminal fragment in SR. Our results indicate that synthetic domain peptides can mimic a native, ligand-binding conformation in vitro and that the dantrolene-binding site and the epitope for the monoclonal antibody on RyR1 are equivalent and composed of amino acids 590-609.
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PMID:Identification of a dantrolene-binding sequence on the skeletal muscle ryanodine receptor. 1216 62

McArdle disease, known as type V glycogen storage disease, is a rare skeletal muscle disorder. Patients with McArdle disease lack skeletal muscle specific glycogen phosphorylase, and myophosphorylase. This subsequently leads to an elevation in serum creatine kinase levels, and results in suffering from exercise intolerance. They have such anesthesiological problems as follows; rhabdomyolysis, myoglobinuria, acute renal failure, and a higher risk of developing malignant hyperthermia. We report a case of general anesthesia for a patient with McArdle disease. The patient was a 38-year-old woman who underwent dilation and curettage. Anesthesia was induced by intravenous administrations of fentanyl and propofol. For maintenance of anesthesia, we used total intravenous anesthesia with propofol. We avoided the use of neuromuscular blockades throughout the operation. There were no signs of rhabdomyolysis, myoglobinuria, worsening muscle weakness, or occurrence of malignant hyperthermia in the perioperative period, and the patient recovered uneventfully.
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PMID:[Anesthesia in a Patient with McArdle Disease]. 2668 76