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)

Analysis of the primary structure of the rabbit skeletal muscle ryanodine receptor led to the identification of two molecules of 5032 and 5037 residues, respectively. Such a sequence discrepancy is likely to be due to the alternative splicing of a 15 bp exon (1) encoding a 5 amino acid insertion (Ala-Gly-Asp-Ala-Gln) after residue 3479. By using PCR on first strand cDNA, we searched for the 15 base pair insertion in the ryanodine receptor mRNA from adult slow- and fast-twitch skeletal muscle, as well as from fast-muscles, at various stages of post-natal development. All rabbit skeletal muscle mRNAs, regardless of their developmental stage and twitch properties, contain two RYR transcripts, suggesting the coexistence of two RYR isoforms in mammalian skeletal muscle.
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PMID:Identification of two ryanodine receptor transcripts in neonatal, slow-, and fast-twitch rabbit skeletal muscles. 794 21

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.
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PMID:Monoclonal antibody to skeletal muscle ryanodine receptor detects a polypeptide in rat brain: comparison of immunogenic fragments after limited proteolysis. 801 88

The expression of the dihydropyridine (DHP) and ryanodine receptors in skeletal muscle was investigated during development of rat myotubes in culture as well as during embryonic and postnatal development in the rat. Through the use of specific gene probes, antibodies and radioligand binding ([3H]PN 200-110 (DHP) and [3H]ryanodine), we identified a significant difference between the time course of appearance of the DHP receptor and the ryanodine receptor during muscle development. Although the number of DHP receptors dramatically increased at early stages of development (up to day 7 in tissue culture and day 20 postnatal), increase in the ryanodine receptor density occurred comparatively later at day 10 in culture and day 30 postnatal. This process was associated with parallel changes in the expression of the mRNA encoding the alpha 1, alpha 2, and beta subunits of the DHP receptor and the skeletal muscle ryanodine receptor. The genes encoding the DHP receptor subunits were activated in a temporally distinct transcript appeared and plateaued first, at the onset of myoblast fusion and day 16 embryonic. This was followed closely by an increase in expression of the mRNAs for alpha 1 and alpha 2 subunits which coincided with the sharp rise in the DHP receptor density. Ryanodine receptor gene expression was induced well after the DHP receptor gene expression had plateaued. The temporal appearance of the polypeptides comprising the DHP receptor subunits and the ryanodine receptor paralleled the induction of the genes encoding these receptors. These results imply that gene expression is a major mechanism that contributes to the regulation of DHP and ryanodine receptor numbers during muscle development. The temporal differences in the induction of the genes encoding the DHP receptor subunits and the ryanodine receptor suggests that these genes are under the control of distinct endogenous factors. These differences in expression of the DHP receptor and the ryanodine receptor may contribute to the different mechanisms of excitation-contraction coupling in immature versus adult skeletal muscle.
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PMID:Temporal differences in the induction of dihydropyridine receptor subunits and ryanodine receptors during skeletal muscle development. 806 21

We have shown previously that the skeletal muscle ryanodine receptor mRNA of approximately 16,000 nucleotides codes 5,037 amino acid residues constituting the calcium release channel in skeletal muscle. In this study, RNA blot hybridization analysis shows that the brain contains an RNA species with an estimated size of approximately 2,400 nucleotides hybridizable with the 3'-terminal region of the skeletal muscle ryanodine receptor cDNA. cDNA cloning and genome analysis indicated that two transcripts differing in their start sites are produced from the skeletal muscle ryanodine receptor gene in a tissue-specific fashion, and that the mRNA in brain may code the carboxyl-terminal region of the ryanodine receptor molecule. cDNA expression experiments suggested that the ATG triplet encoding Met4382 of the skeletal muscle ryanodine receptor can function as a translation initiation codon, and that the expressed protein composed of the carboxy terminal 656 amino acid residues of the receptor is located on the endoplasmic reticulum membrane.
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PMID:A brain-specific transcript from the 3'-terminal region of the skeletal muscle ryanodine receptor gene. 809 30

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

Antibodies were raised against synthetic peptides corresponding to the N-terminal (residues 2-15) and the C-terminal (residues 5027-5037) parts of the rabbit skeletal muscle ryanodine receptor. The specificity of the antibodies generated was tested by e.l.i.s.a., Western blotting and immunofluorescence. All these tests demonstrated the specificity of the antibodies and their ability to react with both the native and the denaturated ryanodine receptor. Both the anti-N-terminus and the anti-C-terminus antibodies bound to sarcoplasmic reticulum vesicles, indicating that each end of the membrane-embedded ryanodine receptor is exposed to the cytoplasmic side of the vesicles. These immunological data were complemented with proteolysis experiments using carboxypeptidase A. Carboxypeptidase A induced degradation of the C-terminal end of the ryanodine receptor in sarcoplasmic reticulum vesicles and a concomitant loss of reactivity of the anti-C-terminus antibodies in Western blots, providing extra evidence for the cytoplasmic localization of the C-terminal end of the ryanodine receptor.
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PMID:Transmembrane orientation of the N-terminal and C-terminal ends of the ryanodine receptor in the sarcoplasmic reticulum of rabbit skeletal muscle. 814 92

Ryanodine receptors/Ca2+ release channels play an important role in regulating the intracellular free calcium concentrations in both muscle and nonmuscle cells. Ryanodine, a neutral plant alkaloid, specifically binds to and modulates these Ca2+ release channels. In the work described here, we characterize the interaction of a tritium-labeled, photoactivable derivative of ryanodine (3H-labeled 10-O-[3-(4-azidobenzamido)propionyl]ryanodine ([3H]ABRy)) with the ryanodine receptor of skeletal, cardiac, and brain membranes. Scatchard analysis demonstrates that this ligand binds to a single class of high affinity sites in skeletal muscle triads. Furthermore, competition binding assays of [3H]ryanodine with skeletal, cardiac, and brain membranes in the presence of increasing concentrations of unlabeled ABRy illustrate that this azido derivative of ryanodine is able to specifically displace [3H]ryanodine from its binding site(s). Analysis of the effects of Ca2+, ATP, and KCl on [3H]ABRy binding in triad membranes shows a similar modulation of binding to that seen in these membranes with [3H]ryanodine. Photoaffinity labeling of triads with [3H]ABRy resulted in specific and covalent incorporation of [3H]ABRy into a 565-kDa protein that was shown to be the skeletal muscle ryanodine receptor. Digestion of the labeled ryanodine receptor revealed a [3H]ABRy-labeled 76-kDa tryptic fragment that was identified with an antibody directed against the COOH-terminal of the receptor. These results demonstrate that the 76-kDa COOH-terminal tryptic fragment contains the high affinity binding site for ryanodine.
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PMID:Photoaffinity labeling of the ryanodine receptor/Ca2+ release channel with an azido derivative of ryanodine. 817 31

Excitation-contraction coupling in skeletal muscle is mediated by two calcium channels located in the membranes of the transverse tubule and the sarcoplasmic reticulum. Calcium is released from the terminal cisternae of the sarcoplasmic reticulum via the ryanodine receptor. Abnormal increases in myoplasmic free calcium caused by a defect in the ryanodine receptor have been reported in malignant hyperthermia. Malignant hyperthermia is a life-threatening pharmacogenetic disorder in a variety of species and is triggered by volatile anesthetics and depolarizing muscle relaxants. To study the genomic organization of the porcine skeletal muscle ryanodine receptor gene, we have isolated six genomic fragments spanning approximately 80 kb of chromosomal DNA. In this report, we describe the genomic organization of a 15.5-kb genomic fragment comprising 18 exons coding for region 4624 to 7929 of the porcine skeletal muscle ryanodine receptor gene.
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PMID:Genomic organization of the porcine skeletal muscle ryanodine receptor (RYR1) gene coding region 4624 to 7929. 828 38

Calcium release from intracellular stores is the signal generated by numerous regulatory pathways including those mediated by hormones, neurotransmitters and electrical activation of muscle. Recently two forms of intracellular calcium release channels (CRCs) have been identified. One, the inositol 1,4,5-trisphosphate receptors (IP3Rs) mediate IP3-induced Ca2+ release and are believed to be present on the ER of most cell types. A second form, the ryanodine receptors (RYRs) of the sarcoplasmic reticulum, have evolved specialized functions relevant to muscle contraction and are the major CRCs found in striated muscles. Though structurally related, IP3Rs and RYRs have distinct physiologic and pharmacologic profiles. In the heart, where the dominant mechanism of intracellular calcium release during excitation-contraction coupling is Ca(2+)-induced Ca2+ release via the RYR, a role for IP3-mediated Ca2+ release has also been proposed. It has been assumed that IP3Rs are expressed in the heart as in most other tissues, however, it has not been possible to state whether cardiac IP3Rs were present in cardiac myocytes (which already express abundant amounts of RYR) or only in non-muscle cells within the heart. This lack of information regarding the expression and structure of an IP3R within cardiac myocytes has hampered the elucidation of the significance of IP3 signaling in the heart. In the present study we have used combined in situ hybridization to IP3R mRNA and immunocytochemistry to demonstrate that, in addition to the RYR, an IP3R is also expressed in rat cardiac myocytes. Immunoreactivity and RNAse protection have shown that the IP3R expressed in cardiac myocytes is structurally similar to the IP3R in brain and vascular smooth muscle. Within cardiac myocytes, IP3R mRNA levels were approximately 50-fold lower than that of the cardiac RYR mRNA. Identification of an IP3R in cardiac myocytes provides the basis for future studies designed to elucidate its functional role both as a mediator of pharmacologic and hormonal influences on the heart, and in terms of its possible interaction with the RYR during excitation-contraction coupling in the heart.
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PMID:Inositol 1,4,5-trisphosphate receptor expression in cardiac myocytes. 838 5

The photoaffinity analog of ATP, 3'-O-(4-benzoyl)benzoyl-adenosine 5'-triphosphate (Bz2ATP) was used to covalently label and to identify the ATP binding site of the skeletal muscle ryanodine receptor. Like ATP, Bz2ATP stimulates up to fivefold the binding of ryanodine to its receptor. Photoactivation by ultraviolet light of the benzophenone group in the [alpha-32P]Bz2ATP results in covalent binding of [alpha-32P]Bz2ATP to the 450-kDa polypeptide, the ryanodine receptor's subunit. An apparent molar stiochiometry of Bz2ATP to the tetrameric ryanodine receptor complex of 1.146 +/- 0.087 (n = 2) was estimated. The covalent binding of [alpha-32P]Bz2ATP was inhibited by ATP and analogous compounds in the order: ATP = AdoPP[CH2]P = ADP = Ado = cAMP > AMP > ITP = GTP. Similar specificity was obtained for the stimulation of ryanodine binding by these nucleotides. ATP increased the ryanodine binding affinity by about sixfold. The polycationic dye ruthenium red, known as an inhibitor of Ca2+ release and ryanodine binding, inhibited the labeling of the ryanodine receptor by [alpha-32P]Bz2ATP. Tryptic digestion of the ryanodine receptor revealed a [alpha-32P]Bz2ATP-labeled 76-kDa tryptic fragment. Digestion of either the [alpha-32P]Bz2ATP-labeled 450-kDa or the 76-kDa polypeptides with S. aureus resulted in the appearance of four labeled fragments of 39, 33, 27 and 13 kDa, where the 39-kDa fragment is the precursor of the 27-kDa and 13-kDa fragments. The results suggest that the regulation of Ca2+ release by ATP involves an ATP binding site(s) located on the 27-kDa and 13-kDa fragments of the ryanodine receptor protein.
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PMID:Characterization and photoaffinity labeling of the ATP binding site of the ryanodine receptor from skeletal muscle. 838 21


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