Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P21817 (RyR1)
 1,154 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The fluorogenic maleimide 7-diethylamino-3-(4'-maleimidylphenyl)-4-methylcoumarin (CPM) has been shown to selectively form Michael adducts with hyperreactive sulfhydryls on the skeletal sarcoplasmic reticulum (SR) ryanodine receptor (RyR1) and triadin which are essential for normal Ca2+ channel function (Liu, G., Abramson, J.J., Zable, A.C., and Pessah, I.N. (1994) Mol. Pharmacol. 45, 189-200). The present report demonstrates a functionally important interaction between RyR1 and triadin which involves, in part, redox cycling of hyperreactive sulfhydryls in response to channel activation and inactivation. Nanomolar CPM is shown to selectively label RyR1 and triadin only in the presence of Ca2+ channel inhibitors (Mg2+, neomycin, ruthenium red, or anti-triadin antibody). Treatment of SR with channel activators (micromolar Ca2+, nanomolar ryanodine, or millimolar caffeine), 1) slows CPM labeling kinetics > 10-fold, 2) negates CPM labeling of channel-associated sulfhydryls, and 3) stabilizes a high molecular weight complex (HMWC) which appears on nonreducing SDS-polyacrylamide gel electrophoresis gels. The HMWC is positively identified as RyR1 and triadin by Western blot and immunoprecipitation analyses. High-affinity [3H]ryanodine-binding sites are immunoprecipitated by either anti-RyR1 or anti-triadin antibody dose dependently. 1,4-Naphthoquinone (< or = 40 pmol/micrograms protein) selectively oxidizes hyperreactive sulfhydryls on RyR1 and triadin, induces Ca2+ efflux from SR, and stabilizes the HMWC. The HMWC is reduced by beta-mercaptoethanol or dithiothreitol into its component RyR1 and triadin promoters. The results provide direct evidence for the existence of a functionally important complex between RyR1 and triadin whose stability is determined by the redox state of hyperreactive sulfhydryl moieties which are allosterically regulated by physiological and pharmacological channel ligands. The present results suggest a possible molecular mechanism by which localized transient changes in the redox state within the RyR1-triadin complex can signal information across the SR membrane.
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PMID:Molecular interaction between ryanodine receptor and glycoprotein triadin involves redox cycling of functionally important hyperreactive sulfhydryls. 780 31

Malignant hyperthermia (MH) is a potentially fatal autosomal dominant disorder of skeletal muscle and is triggered in susceptible people by all commonly used inhalational anaesthetics and depolarizing muscle relaxants. To date, six mutations in the skeletal muscle ryanodine receptor gene (RYR1) have been identified in malignant hyperthermia susceptible (MHS) and central core disease (CCD) cases. Using SSCP analysis, we have screened the RYR1 gene in affected individuals for novel MHS mutations and have identified a G to A transition mutation which results in the replacement of a conserved Gly at position 2433 with an Arg. The Gly2433Arg mutation was present in four of 104 unrelated MHS individuals investigated and was not detected in a normal population sample. This mutation is adjacent to the previously identified Arg2434His mutation reported in a CCD/MH family and indicates that there may be a second region in the RYR1 gene where MHS/CCD mutations cluster.
Hum Mol Genet 1994 Oct
PMID:Detection of a novel RYR1 mutation in four malignant hyperthermia pedigrees. 784 12

Single strand conformational polymorphism analysis was used to screen exons 43 and 44 in the skeletal muscle ryanodine receptor gene from 17 positively diagnosed members of families in which chromosome 19-linked malignant hyperthermia (MH) was segregating. A polymorphism in two unrelated individuals was found to result from the substitution of A for G7297, leading to the substitution of Arg for Gly2433. This mutation is adjacent to a mutation (Arg2434 to His) previously linked to MH and central core disease (Y. Zhang et al., Nature Genet. 1993, 5, 46-50). Subsequent screening showed the presence of the mutation in four of 106 MH families tested and its absence from about 1000 other chromosomes. The mutation was present in all six individuals in four families who had had an MH reaction, in two obligate carriers and in 10 individuals diagnosed as MH susceptible by the caffeine/halothane contracture test (CHCT). The mutation was present in an individual with a normal response to the CHCT and was absent in three individuals with a positive CHCT response. These discrepancies would be consistent with inaccuracies in the CHCT and/or with segregation of a second MH allele within two of the four affected families.
Hum Mol Genet 1994 Dec
PMID:The substitution of Arg for Gly2433 in the human skeletal muscle ryanodine receptor is associated with malignant hyperthermia. 788 17

A polypeptide of high molecular mass has been detected in mammalian brain by a monoclonal antibody, 5C3, raised against skeletal muscle ryanodine receptor. 5C3 does not crossreact with the cardiac ryanodine receptor, the isoform which is believed to be located in many regions of the brain. Endogenous proteases in brain formed a prominent immunogenic fragment of 116 kDa whereas five immunostaining polypeptides greater than 200 kDa were observed in skeletal muscle. Mild trypsin digestion of brain microsomes resulted in fragments of approximately 400 and approximately 280 kDa, of similar mass to two peptides formed from the skeletal muscle ryanodine receptor. However a peptide of 28 kDa, resistant to trypsin, was observed in muscle but not in brain. The brain polypeptide recognised by 5C3 is therefore not identical to the skeletal muscle ryanodine receptor.
Biochem Mol Biol Int 1994 Jan
PMID:Monoclonal antibody to skeletal muscle ryanodine receptor detects a polypeptide in rat brain: comparison of immunogenic fragments after limited proteolysis. 801 88

Two novel natural ryanoids from extracts of the wood of Ryania speciosa Vahl were evaluated with sarcoplasmic reticulum (SR) vesicles for their binding affinities and their activating and deactivating effects on Ca2+ release channels. The new ryanoids, which are more polar than the known Ryania constituents ryanodine and didehydro-(9,21)-ryanodine, were purified using silica gel column chromatography and reverse phase high performance liquid chromatography. The new ryanoids were designated ester E and ester F, in keeping with nomenclature previously used in the literature. These compounds were identified by NMR spectroscopy and mass spectroscopy as C9ax-hydroxyryanodine and C8ax-hydroxy-C10-epi-dehydroryanodine, respectively. Binding of esters E and F to the high affinity (nanomolar Kd) site on SR Ca2+ release channels was determined from relative binding affinity assays using 6.7 nM [3H]ryanodine. Apparent Kd values of ryanodine, ester E, and ester F for binding to this domain on the skeletal muscle ryanodine receptor/SR Ca2+ release channel were 4.4 +/- 0.8, 65 +/- 10, and 257 +/- 53 nM, respectively (mean +/- standard deviation, four or more experiments). Apparent Kd values for cardiac muscle receptors were 0.51 +/- 0.01, 12 +/- 0.4, and 57 nM, respectively. As a functional indication of the effects of the ryanoids, channel-opening (activator) and channel-closing (deactivator) actions were assessed from the ability of the ryanoids to alter the rate of Ca2+ efflux from passively loaded skeletal muscle junctional sarcoplasmic reticular vesicles (JSRV). Activator actions among the ryanoids were similar, in that they exhibited apparently parallel concentration-effect curves, having a slope of 40% Ca2+ loss/decade increment in ryanoid concentration. Half-maximal values for activation (EC50 values) were 2.5, 63, and 43 microM for ryanodine, ester E, and ester F, respectively. Maximal channel opening by ester E was significantly less than that produced by the other ryanoids. The deactivator actions of the compounds on skeletal JSRV were dissimilar, in that their concentration-effect curves appeared not to be parallel. The quotient of the EC50 for deactivation and that for activation was taken as the concentration-coupling ratio (CCR). The CCR for ryanodine was 114 and that for ester F was 72, but the CCR for ester E was only 21. ATP-dependent Ca2+ accumulation by cardiac JSRV provided a second means to evaluate deactivator actions of the ryanoids. Results from cardiac JSRV assays were in general similar to those from skeletal JSRV assays.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Pharmacol 1993 Aug
PMID:Differential activating and deactivating effects of natural ryanodine congeners on the calcium release channel of sarcoplasmic reticulum: evidence for separation of effects at functionally distinct sites. 839 96

We investigated the mRNA distribution of three different ryanodine receptors (RyR) and of the intracellular Ca(2+)-release channel/inositol 1,4,5-trisphosphate receptor (IP3R) type 1 in the rat heart during development and aging. In situ hybridization analysis shows that RyR1 mRNA is never expressed in the heart at any of the stages examined: RyR2 mRNA is detectable in cardiomyocytes in the early embryonic stages, whereas RyR3 mRNA accumulates in cardiomyocytes around birth. IP3R mRNA appears at first in the primitive atrium at embryonic day 11 and in subsequent stages it is detectable also in a minor population of ventricular myocytes, which presumably correspond to conduction system precursors. In the adult heart, no apparent difference in hybridization signal intensity is observed between atrial and ventricular working myocytes either with RyR2, RyR3 or IP3R cRNA probes, except for myocytes of the heart conduction system, which differ from working myocytes in the intensity of the hybridization signals for each probe. Additional differences are detected in the senescent heart with the IP3R cRNA probe, which hybridizes with atrial myocytes stronger than with ventricular ones. RNase protection analysis confirms the temporal differences in RyR2 and RyR3 transcript accumulation observed during heart development and reveals a significant increase of IP3R mRNA in the atrial myocardium during aging. Thus, the composition of intracellular Ca(2+)-release channel mRNAs of the rat heart shows temporal and regional variations: such changes might reflect important differences in transcriptional regulation of these genes among myocytes.
J Mol Cell Cardiol 1997 Mar
PMID:Regional and age-related differences in mRNA composition of intracellular Ca(2+)-release channels of rat cardiac myocytes. 915 63

Malignant hyperthermia (MH) is an autosomal dominant disorder which is potentially lethal in susceptible individuals on exposure to commonly used inhalational anaesthetics and depolarising muscle relaxants. Crises reflect the consequences of disturbed skeletal muscle calcium homeostasis. Susceptibility was first localised to chromosome 19q13.1 and the skeletal muscle ryanodine receptor, RYR1 (the calcium release channel of the sarcoplasmic reticulum). Defects in this gene have been identified which cosegregate with the MHS phenotype and evidence as to their potential causal roles has accumulated. MH has, however, been shown to be genetically heterogeneous, additional loci on chromosomes 3q, 17q and 7q being proposed. Pedigrees remain in Europe where linkage status is still unclear. In a collaborative search of the human genome conducted with three pedigrees whose disease status was classified according to the European IVCT protocol we have evidence to suggest that at least two further loci exist for MH susceptibility. One of these locates to chromosome 1q, the site of a candidate gene, CACNL1A3, encoding the alpha-subunit of the dihydropyridine receptor. The second region resides on chromosome 5p to where no known candidate has been mapped to date. The third family exhibited inconclusive results which suggests the existence of at least one other locus. This study adds to the evidence for considerable genetic heterogeneity in MH and will provide a route to further our understanding of the molecular pathology of the condition.
Hum Mol Genet 1997 Jun
PMID:A genome wide search for susceptibility loci in three European malignant hyperthermia pedigrees. 917 45

The skeletal muscle ryanodine receptor (RYR1) is a calcium release channel that mediates efflux of calcium ions from the sarcoplasmic reticulum into the myoplasm during excitation-contraction coupling. Mutations in the RYR1 gene have been detected in about 50% of the patients suffering from malignant hyperthermia (MH), but evidence is accumulating that other genetic defects can also lead to MH in humans. MH is a life-threatening disorder induced by exposure to volatile anesthetics and/or the muscle relaxans succinylcholin during surgical procedures in affected patients. MH leads to skeletal muscle rigidity, hypermetabolism and rapid rise in body temperature. MH is also known in pigs where it is triggered by stress and therefore often referred to as porcine stress syndrome. The existence of an animal model has greatly faciliated the elucidation of the basis for the human disease. This review describes recent advances in the understanding of the physiological action of ryanodine receptors and new insights regarding the relation between different RYR1 mutations and distinct phenotypical appearances.
Int J Mol Med 1998 Sep
PMID:Ryanodine receptors and their role in genetic diseases (review). 985 1

Ryanodine receptors are a family of intracellular Ca2+ release channel proteins, which exist as tetrameric complexes of large ( approximately 5000 amino acid residue) polypeptide monomers. As well as controlling striated muscle contraction and neurotransmitter release, these channel proteins have been implicated in several pathological states. In order to characterise ryanodine receptors in various tissues, mouse monoclonal antibodies were developed against the type 1 isoform isolated from skeletal muscle. Several of these antibodies recognise ryanodine receptor in skeletal muscle, as well as high molecular weight (k-HMW) protein in kidney microsomes. Like the ryanodine receptor, the k-HMW protein binds 45Ca2+ and sediments as a large complex upon sucrose density-gradient centrifugation. In contrast, the k-HMW protein does not bind ryanodine and is glycosylated. Furthermore, monoclonal and polyclonal antibodies generated against purified k-HMW protein do not recognise skeletal muscle ryanodine receptor. Characterisation of a cDNA clone encoding part of the k-HMW protein revealed that it is likely to be the rabbit homologue of human megalin, an autoimmune antigen in membranous glomerulonephritis. Potential consequences of immunological similarities between ryanodine receptors and megalin are discussed in terms of autoimmune disease.
Int J Mol Med 1999 Jun
PMID:Autoimmune antigen megalin displays similarities with skeletal muscle ryanodine receptor/Ca2+ release channel. 1034 Dec 94

Malignant hyperthermia (MH) in man is an autosomal dominant disorder of skeletal muscle Ca(2+)-regulation. During anesthesia in predisposed individuals, it is triggered by volatile anesthetics and depolarizing muscle relaxants. In >50% of the families, MH susceptibility is linked to the gene encoding the skeletal muscle ryanodine receptor (RYR1), the calcium release channel of the sarcoplasmic reticulum, on chromosome 19q12-13.2. To date, 21 RYR1 mutations have been identified in a number of pedigrees. Four of them are also associated with central core disease (CCD), a congenital myopathy. Screening for these 21 mutations in 105 MH families including 10 CCD families phenotyped by the in vitro contracture test (IVCT) according to the European protocol revealed the following approximate distribution: 9% Arg-614-Cys, 1% Arg-614-Leu, 1% Arg-2163-Cys, 1% Val-2168-Met, 3% Thr-2206-Met and 7% Gly-2434-Arg. In one CCD family, the disease was caused by a recently reported MH mutation, Arg-2454-His. Two novel mutations, Thr-2206-Arg and Arg-2454-Cys were detected, each in a single pedigree. In the 109 individuals of the 25 families with RYR1 mutations cosegregation between genetic result and IVCT was almost perfect, only three genotypes were discordant with the IVCT phenotypes, suggesting a true sensitivity of 98.5% and a specificity of minimally 81.8% for this test. Screening of the transmembraneous region of RYR1 did not yield a new mutation confirming the cytosolic portion of the protein to be of main functional importance for disease pathogenesis.
Hum Mol Genet 1999 Oct
PMID:Screening of the ryanodine receptor gene in 105 malignant hyperthermia families: novel mutations and concordance with the in vitro contracture test. 1048 75


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