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)

Expression studies with skeletal and cardiac muscle cDNAs have suggested that the putative cytoplasmic loop region of the dihydropyridine receptor (DHPR) alpha 1 subunit between transmembrane repeats II and III (DCL) is a major determinant of the type of excitation-contraction coupling (skeletal or cardiac) in rescued dysgenic muscle cells (Tanabe, T., Beam, K. G., Adams, B. A., Niidome, T., and Numa, S. (1990) Nature 346, 567-569). In this study, the possibility of a direct functional interaction with the sarcoplasmic reticulum ryanodine receptor/Ca2+ release channel has been tested by expressing the DCLs of the mammalian skeletal and cardiac muscle DHPR alpha 1 subunit in Escherichia coli. The purified peptides activated the skeletal muscle ryanodine receptor/Ca2+ release channel in single channel and [3H]ryanodine binding measurements, by increasing channel open probability and the affinity of [3H]ryanodine binding, respectively. The two peptides did not activate the cardiac muscle Ca2+ release channel. Other proteins (polylysine, serum albumin) also increased [3H]ryanodine binding and Ca2+ release channel activity, but their activation mechanisms were distinguishable from DCLs. These results show that the II-III cytoplasmic loop of the skeletal and cardiac DHPR alpha 1 subunit functionally interacts with the skeletal, but not cardiac, muscle Ca2+ release channel. Furthermore, our studies suggest that in addition to the DHPR, the sarcoplasmic reticulum Ca2+ release channel may determine the type of E-C coupling that exists in muscle.
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PMID:Activation of the skeletal muscle calcium release channel by a cytoplasmic loop of the dihydropyridine receptor. 812 2

Activation of intracellular Ca(2+)-release channels/ryanodine receptors (RyRs) is a fundamental step in the regulation of muscle contraction. In mammalian skeletal muscle, Ca(2+)-release channels containing the type 1 isoform of RyR (RyR1) open to release Ca2+ from the sarcoplasmic reticulum (SR) upon stimulation by the voltage-activated dihydropyridine receptor on the T-tubule/plasma membrane. In addition to RyR1, low levels of the mRNA of the RyR3 isoform have been recently detected in mammalian skeletal muscles. Here we report data on the distribution of the RyR3 gene product in mammalian skeletal muscles. Western-blot analysis of SR of individual muscles indicated that, at variance with the even distribution of the RyR1 isoform, the RyR3 content varies among different muscles, with relatively higher amounts being detected in diaphragm and soleus, and lower levels in abdominal muscles and tibialis anterior. In these muscles RyR3 was localized in the terminal cisternae of the SR. No detectable levels of RyR3 were observed in the extensor digitorum longus. Preferential high content of RyR3 in the diaphragm muscle was observed in several mammalian species. In situ hybridization analysis demonstrated that RyR3 transcripts are not restricted to a specific subset of skeletal-muscle fibres. Differential utilization of the RyR3 isoform in skeletal muscle may be relevant to the modulation of Ca2+ release with respect to specific muscle-contraction properties.
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PMID:Differential distribution of ryanodine receptor type 3 (RyR3) gene product in mammalian skeletal muscles. 864 4

Malignant hyperthermia (MH) is a potentially fatal, inherited pharmacogenetic disorder characterised by a dysfunction of the intracellular calcium regulation. Linkage to DNA markers from the chromosome 19q12-13.2 region and the MHS-phenotype (MH susceptible) has been shown in about 50% of families with a history of MH. The ryanodine receptor gene encoding the human skeletal muscle ryanodine receptor has been localised to the chromosome 19q13.1-13.2 region. The ryanodine receptor, which is an intracellular calcium release channel, has been proposed to be one of the candidate structures for the MH defect. At present, eight different single point mutations have been identified in the human skeletal muscle ryanodine receptor gene in families with disposition to MH. The incidence of the various mutations has been reported as 2-10% each. A combination of different mutations within one pedigree has not been demonstrated. A few years ago, linkage of the MHS-phenotype to DNA markers from the chromosome 17q11.2-24 region was published by an American group. However, this observation has not been confirmed in any of the several European families susceptible to MH. Genes encoding for subunits of the dihydropyridine receptor and the sodium channel of the human skeletal muscle have been found to be located in the chromosome 17q11.2-24 region which, in fact, could be additional candidates for the MH defect. The dihydropyridine receptor is linked to the ryanodine receptor and involved in the calcium regulation of skeletal muscle. Very recent studies have shown linkage to DNA markers from chromosome 7q- and chromosome 3q13.1 regions and the MHS phenotype in two distinct families with history of MH. However, the relevance of this observation is so far unknown. At present, unambiguous preoperative screening of MH disposition based on molecular genetic characteristics is not available because of the enormous heterogeneity of the human MH syndrome. Thus, the halothane-caffeine in-vitro contracture test according to the standard protocol of the "European MH Group" must be performed in order to discover MH susceptibility.
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PMID:[What significance to genotype changes have in diagnosis of malignant hyperthermia?]. 896 26

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.
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PMID:A genome wide search for susceptibility loci in three European malignant hyperthermia pedigrees. 917 45

Interactions between the Ca2+ release channel of skeletal muscle sarcoplasmic reticulum (ryanodine receptor or RyR1) and the loop linking domains II and III (II-III loop) of the skeletal muscle L-type Ca2+ channel (dihydropyridine receptor or DHPR) are critical for excitation-contraction coupling in skeletal muscle. The DHPR II-III loop was fused to glutathione S-transferase- or His-peptide and used as a protein affinity column for 35S-labeled in vitro translated fragments from the N-terminal three-fourths of RyR1. RyR1 residues Leu922-Asp1112 bound specifically to the DHPR II-III loop column, but the corresponding fragment from the cardiac ryanodine receptor (RyR2) did not. The use of chimeras between RyR1 and RyR2 localized the interaction to 37 amino acids, Arg1076-Asp1112, in RyR1. The RyR1 922-1112 fragment did not bind to the cardiac DHPR II-III loop but did bind to the skeletal muscle Na+ channel II-III loop. The skeletal DHPR II-III loop double mutant K677E/K682E lost most of its capacity to interact with RyR1, suggesting that two positively charged residues are important in the interaction between RyR and DHPR.
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PMID:A 37-amino acid sequence in the skeletal muscle ryanodine receptor interacts with the cytoplasmic loop between domains II and III in the skeletal muscle dihydropyridine receptor. 952 69

We have previously shown that among several peptides encompassing various regions of the II-III loop of the dihydropyridine receptor alpha 1 subunit, only one peptide corresponding to the Thr671-Leu690 region (designated as peptide A) activated ryanodine binding to and induced calcium release from the sarcoplasmic reticulum [El-Hayek et al. (1995) J. Biol. Chem. 270, 22116-22118]. To further localize within peptide A the minimum unit essential for activating the sarcoplasmic reticulum calcium release channel, we synthesized variously truncated forms of peptide A and examined their ability to activate ryanodine binding. We found that the carboxy-terminal 10-residue region of peptide A encompassing Arg681-Leu690 (peptide As-10; s, skeletal muscle-type sequence) activated ryanodine binding in a RyR1-specific manner and induced calcium release even more efficiently than the 20-residue peptide A. Further truncation of one or more residue(s) of peptide As-10 virtually abolished both functions of activating ryanodine binding and inducing Ca2+ release. The activating ability of As-10 seems to be determined by at least two factors: (1) the distribution of the positively charged residues, and (2) the skeletal muscle-type amino acid sequence, as deduced from the comparison of various peptides with modified structures. These results provide evidence that the minimum essential unit for the in situ trigger of skeletal muscle excitation-contraction coupling is localized in the Arg681-Leu690 region of the II-III loop of the alpha 1 subunit of the dihydropyridine receptor.
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PMID:Identification of the minimum essential region in the II-III loop of the dihydropyridine receptor alpha 1 subunit required for activation of skeletal muscle-type excitation-contraction coupling. 957 89

Excitation-contraction uncoupling has been identified as a mechanism underlying skeletal muscle weakness in aging mammals (sarcopenia). The basic mechanism for excitation-contraction uncoupling is a larger number of ryanodine receptors (RyR1) uncoupled to dihydropyridine receptors (DHPRs) (Delbono, O., O'Rourke, K. S., and Ettinger, W. H. (1995) J. Membr. Biol. 148, 211-222). In the present study, we used transgenic mice overexpressing human insulin-like growth factor-1 exclusively in skeletal muscle to test the hypothesis that a high concentration of IGF-1 prevents age-related decreases in DHPR number and in muscle force. Transgenic mice express 10-20-fold higher IGF-1 concentrations than nontransgenic mice at all ages (1-24 months). The number of DHPRs is 50-100% higher, and the DHPR/RyR1 ratio is 40% higher in transgenic soleus (predominantly type I fiber muscles), extensor digitorum longus (predominantly type II fiber muscles), and the pool of type I and type II fiber muscles than in nontransgenic young (6 months), adult (12 months), and old (24 months) mice. Furthermore, no age-related changes in DHPRs and the DHPR/RyR1 ratio were observed in transgenic muscles. The specific single twitch and tetanic muscle force in old transgenic soleus and extensor digitorum longus muscles are 50% higher than in old nontransgenic muscles. Taken together, these results support the concept that IGF-1- dependent prevention of age-related decline in DHPR expression is associated with stronger muscle contraction in older transgenic mice.
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PMID:Overexpression of IGF-1 exclusively in skeletal muscle prevents age-related decline in the number of dihydropyridine receptors. 978 85

The dihydropyridine receptor (DHPR) and ryanodine receptor (RYR1) are needed for excitation-contraction coupling in skeletal muscle. Previous studies from this laboratory have shown DHPR-RYR1 uncoupling in 33-month-old Fischer 344 x Brown Norway F1 (F344BNF1) rats fed ad libitum. The purpose of the present study is to determine whether caloric restriction prevents age-related impairments in skeletal muscle function and expression of DHPR and RyR1. Bundles of soleus and extensor digitorum longus (EDL) were studied from rats fed ad libitum and on 60 percent caloric restriction. Significant differences were found in peak twitch or tetanic tension between the ad libitum and calorie-restricted groups in soleus and EDL muscles. A significant increase in the expression of DHPR and RyR1 was observed in caloric restricted rats. These results show that calorie restriction preserves the mechanical properties of aging hind-limb skeletal muscle and maintains the level of DHPR and RyR1 in aged F344BNF1 rats fed ad libitum.
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PMID:Effectiveness of caloric restriction in preventing age-related changes in rat skeletal muscle. 979 Sep 13

Excitation-contraction coupling in skeletal muscle is a result of the interaction between the Ca2+ release channel of skeletal muscle sarcoplasmic reticulum (ryanodine receptor or RyR1) and the skeletal muscle L-type Ca2+ channel (dihydropyridine receptor or DHPR). Interactions between RyR1 and DHPR are critical for the depolarization-induced activation of Ca2+ release from the sarcoplasmic reticulum, enhancement of DHPR Ca2+ channel activity, and repolarization-induced inactivation of RyR1. The DHPR III-IV loop was fused to glutathione S-transferase (GST) or His-peptide and used as a protein affinity column for 35S-labeled, in vitro translated fragments from the N-terminal three-fourths of RyR1. RyR1 residues Leu922-Asp1112 bound specifically to the DHPR III-IV loop column, but the corresponding fragment from the cardiac ryanodine receptor (RyR2) did not. Construction of chimeras between RyR1 and RyR2 showed that amino acids Lys954-Asp1112 retained full binding activity, whereas Leu922-Phe1075 had no binding activity. The RyR1 sequence Arg1076-Asp1112, previously shown to interact with the DHPR II-III loop (Leong, P., and MacLennan, D., H. (1998) J. Biol. Chem. 273, 7791-7794), bound to DHPR III-IV loop columns, but with only half the efficiency of binding of the longer RyR1 sequence, Lys954-Asp1112. These data suggest that the site of DHPR III-IV loop interaction contains elements from both the Lys954-Phe1075 and Arg1076-Asp1112 fragments. The presence of 4 +/- 0.4 microM GST-DHPR II-III or 5 +/- 0.1 microM His-peptide-DHPR III-IV was required for half-maximal co-purification of 35S-labeled RyR1 Leu922-Asp1112 on glutathione-Sepharose or Ni2+-nitrilotriacetic acid. Dose-dependent inhibition of 35S-labeled RyR1 Leu922-Asp1112 binding to GST-DHPR II-III and GST-DHPR III-IV by His10-DHPR II-III and His-peptide-DHPR III-IV was observed. These studies indicate that the DHPR II-III and III-IV loops bind to contiguous and possibly overlapping sites on RyR1 between Lys 954 and Asp1112.
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PMID:The cytoplasmic loops between domains II and III and domains III and IV in the skeletal muscle dihydropyridine receptor bind to a contiguous site in the skeletal muscle ryanodine receptor. 979 15

Cryo-electron microscopy and three-dimensional, single-particle image analysis have been used to reveal the specific binding site of imperatoxin A (IpTx(a)) on the architecture of the calcium release channel/ryanodine receptor from skeletal muscle (RyR1). IpTx(a) is a peptide toxin that binds with high affinity to RyR1 and affects its functioning. The toxin was derivatized with biotin to enhance its detection with streptavidin. IpTx(a) binds to the cytoplasmic moiety of RyR1 between the clamp and handle domains, 11 nm away from the transmembrane pore. The proposed mimicry by IpTx(a) of the dihydropyridine receptor (DHPR) II-III loop, thought to be a main physiological excitation-contraction trigger, suggests that the IpTx(a) binding location is a potential excitation-contraction signal transduction site.
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PMID:Three-dimensional location of the imperatoxin A binding site on the ryanodine receptor. 1042


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