Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024591 (malignant hyperthermia)
 2,353 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in skeletal ryanodine receptors (sRyR) result in malignant hyperthermia in humans and Porcine Stress Syndrome (PSS) in pigs. Whether the sRyR is expressed in neuronal tissue and what impact it has on neuronal function is relatively unexplored. We have hypothesized that the presence of mutated sRyR may be accompanied by compensatory changes in Ca(2+)-binding protein expression. We were interested in whether pigs heterozygous for mutated sRyR would show changes in the expression of Ca(2+)-binding proteins, in specific regions of the brain, and whether changes in this expression would be accompanied by the presence of sRyR within that region. The objectives of the current experiments were to determine (1) whether calreticulin (CR) and calsequestrin (CS) are expressed in the pituitary gland and brain of the pig, (2) if boars heterozygous for mutated sRyR differed from wild-type boars in the expression of CR or CS, and (3) if altered Ca(2+)-binding protein expression would be accompanied by the presence of sRyR mRNA. Boars either heterozygous or wild-type (n=6) for the mutation in sRyR known to cause PSS, were euthanized and the pituitary gland and brains were collected for western blotting for CR and CS. An additional four wild-type boars were sacrificed and brains were collected for in situ hybridization for sRyR mRNA. Immunoreactive CR was expressed in porcine tissues with highest (p<0.0001) expression in the pituitary gland and lower but equivalent expression in the hypothalamus, frontal cortex, and hippocampus. Immunoreactive CS was not detectable in the pituitary gland while low levels were observed in the hypothalamus and frontal cortex. Dramatically higher (p<0.0001) levels of CS were found in the hippocampus. Genotype did not affect CR expression in the pituitary gland or any brain region examined. Immunoreactive CS levels were lower (p<0.002) in the hippocampus of heterozygous compared to wild-type boars. In situ hybridization experiments revealed the presence of sRyR mRNA in the hippocampus equally distributed across all cell subfields. In conclusion, both CR and CS were expressed in the porcine brain with specific patterns of expression across the brain regions examined. Boars heterozygous for mutated sRyR had lower CS in the hippocampus, which was accompanied by the expression of mRNA for sRyR.
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PMID:The effects of mutated skeletal ryanodine receptors on calreticulin and calsequestrin expression in the brain and pituitary gland of boars. 1064 86

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 microM 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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PMID:Ca2+ signalling and muscle disease. 1095 Nov 87

Mutations in the skeletal muscle RyR1 isoform of the ryanodine receptor (RyR) Ca2+-release channel confer susceptibility to malignant hyperthermia, which may be triggered by inhalational anesthetics such as halothane. Using immunoblotting, we show here that the ryanodine receptor, calmodulin, junctin, calsequestrin, sarcalumenin, calreticulin, annexin-VI, sarco(endo)plasmic reticulum Ca2+-ATPase, and the dihydropyridine receptor exhibit no major changes in their expression level between normal human skeletal muscle and biopsies from individuals susceptible to malignant hyperthermia. In contrast, protein gel-shift studies with halothane-treated sarcoplasmic reticulum vesicles from normal and susceptible specimens showed a clear difference. Although the alpha2-dihydropyridine receptor and calsequestrin were not affected, clustering of the Ca2+-ATPase was induced at comparable halothane concentrations. In the concentration range of 0.014-0.35 mM halothane, anesthetic-induced oligomerization of the RyR1 complex was observed at a lower threshold concentration in the sarcoplasmic reticulum from patients with malignant hyperthermia. Thus the previously described decreased Ca2+-loading ability of the sarcoplasmic reticulum from susceptible muscle fibers is probably not due to a modified expression of Ca2+-handling elements, but more likely a feature of altered quaternary receptor structure or modified functional dynamics within the Ca2+-regulatory apparatus. Possibly increased RyR1 complex formation, in conjunction with decreased Ca2+ uptake, is of central importance to the development of a metabolic crisis in malignant hyperthermia.
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PMID:Increased sensitivity of the ryanodine receptor to halothane-induced oligomerization in malignant hyperthermia-susceptible human skeletal muscle. 1295 58