Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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

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

The Ca2+ release channel of skeletal muscle sarcoplasmic reticulum is modulated in a biphasic manner by the plant alkaloid ryanodine and there are two distinct binding sites on this channel for ryanodine. The Ca2+ release channel is a homotetramer with a subunit of 5037 amino acids. The ability of sarcoplasmic reticulum membranes to bind [3H]ryanodine to the high affinity site is lost upon proteolysis with trypsin. [3H]Ryanodine, however, bound before proteolysis remains bound after trypsin digestion. If the high affinity site is first occupied with [3H]ryanodine and then 100 microM ryanodine is added to occupy the low affinity sites, almost all of [3H]ryanodine bound to the high affinity site remains bound after proteolysis. Proteolysis causes the solubilized Ca2+ release channel containing bound [3H]ryanodine to undergo four discrete shifts in sedimentation (30 S-->28 S-->26 S-->19 S-->14 S). Polypeptides having apparent molecular masses of 76, 66, 56, 45, 37, and 27 kDa can be identified in the 14 S complex. The 76-, 56-, 45-, and 27-kDa polypeptides have been partially sequenced from the NH2 terminus. In addition, the 76-, 66-, and 27-kDa fragments are recognized by an antibody to the last 9 amino acids at the carboxyl terminus of the skeletal muscle ryanodine receptor and the 76-, 66-, and 37-kDa fragments are recognized by an antibody to a peptide matching the sequence 4670-4685. The 56-kDa and the 45-kDa fragments are not Ca2+ release channel fragments. Both high and low affinity ryanodine binding sites are found in the 14 S complex and are, therefore, most likely located between Arg-4475 and the carboxyl terminus.
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PMID:Localization of the high and low affinity [3H]ryanodine binding sites on the skeletal muscle Ca2+ release channel. 819 43

Central core disease (CCD) is a morphologically distinct, autosomal dominant myopathy with variable clinical features. A close association with malignant hyperthermia (MH) has been identified. Since MH and CCD genes have been linked to the skeletal muscle ryanodine receptor (RYR1) gene, cDNA sequence analysis was used to search for a causal RYR1 mutation in a CCD individual. The only amino acid substitution found was an Arg2434His mutation, resulting from the substitution of A for G7301. This mutation was linked to CCD with a lod score of 4.8 at a recombinant fraction of 0.0 in 16 informative meioses in a 130 member family, suggesting a causal relationship to CCD.
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PMID:A mutation in the human ryanodine receptor gene associated with central core disease. 822 Apr 22

Vitamin A (retinol) is a prohormone that exerts its pleiotropic biological effects after conversion into multiple metabolites. In this report we describe the identification of three endogenous, retinolderived effector molecules, 14-hydroxy-retro-retinol (14-HRR), anhydroretinol (AR), and retinoic acid (RA) and a putative storage form of retinol, retinylesters (RE) in the human promyelocytic leukemia cell line HL-60. Exogenous application of the retinol metabolites in retinol-depleted serum-free cultures of HL-60 allowed the identification of unique cellular functions for each metabolite: 14-HRR is a growth factor for HL-60. AR is a functional antagonist of 14-HRR with growth-inhibiting activity, and RA is a potent inducer of granulocyte differentiation accompanied by growth arrest. Finally, intracellular RE serves as storage form allowing continuous production of 14-HRR when no external retinol is available.
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PMID:Growth control or terminal differentiation: endogenous production and differential activities of vitamin A metabolites in HL-60 cells. 824 78

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

14-Hydroxy-4,14-retro-retinol (14-HRR), first isolated from cultures of lymphoblastoid 5/2 and HeLa cells and characterized by NMR, UV, and CD, is a metabolite of retinol which promotes growth of B lymphocytes in culture and activation of T lymphocytes by antigen receptor-mediated signals. It is also produced by various tested cell lines: fibroblasts, leukemia, and Drosophila cells. 14-HRR is the first bioactive retro-retinoid to be discovered and, after retinal and retinoic acid, is the third intracellular messenger molecule derived from retinol. Physical properties and intracellular signaling activities of synthetic (14R)-HRR, (14S)-HRR, and racemic 14-HRR are described. CD spectra indicate that natural 14-HRR isolated previously was a mixture of enantiomers. B-cell survival and T-cell activation assays performed in the optimal range of (7-1.6) x 10(-7) M surprisingly showed that all 14-HRR compounds exhibit similar activity, with the 14R enantiomer exhibiting slightly higher activity in comparison to the 14S enantiomer. However, because of the semiquantitative nature of the assays, the conclusion as to which enantiomer is more active and which is the true ligand for the target receptor must await characterization of this protein.
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PMID:Intracellular signaling activity of synthetic (14R)-, (14S)-, and (14RS)-14-hydroxy-4,14-retro-retinol. 829 89

Vitamin A (retinol) is an essential cofactor for growth of B lymphocytes in culture and for activation of T lymphocytes by antigen receptor-mediated signals. 14-hydroxy-4,14-retro-retinol (14-HRR) a metabolite of retinol, has been implicated as the intracellular mediator of this effect. Anhydroretinol (AR) is a retinol derivative with retro structure produced in activated human B lymphocytes and the insect cell lines SF 21 and Schneider S2. AR reversibly inhibits retinol- and 14-HRR-dependent effects and blocks B lymphocyte proliferation as well as activation of resting T lymphocytes. The intracellular signaling pathway blocked by AR in T cell activation is distinct from the calcineurin/interleukin 2 pathway inhibitable by cyclosporine A or FK-506.
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PMID:Anhydroretinol: a naturally occurring inhibitor of lymphocyte physiology. 834 Jul 62

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


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