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)

In this study, the binding of [3H]ryanodine to liver microsomal subfractions was investigated. The specific binding of [3H]ryanodine, as determined both by vacuum filtration and by ultracentrifugation, is to a single class of high-affinity binding sites with a Kd of 10 +/- 2.5 nM and density of 500 +/- 100 and 1200 +/- 200 fmol/mg of protein by the filtration and centrifugation methods respectively. [3H]Ryanodine binding reached equilibrium in about 1 min and 2 min at 36 degrees C and 24 degrees C respectively, and the half-time of dissociation at 37 degrees C was approx. 15 s. The binding of [3H]ryanodine is Ca(2+)-independent: it is slightly stimulated by NaCl, Mg2+, ATP and InsP3 but strongly inhibited by caffeine, diltiazem and sodium dantrolene. Thus the binding of ryanodine to endoplasmic reticulum membranes shares some of the characteristics of its binding to the sarcoplasmic reticulum but also differs from it in several important properties, such as its Ca(2+)-independence, its rapid association and dissociation, and its inhibition by caffeine. The structural similarities between the skeletal muscle and liver binding sites were further explored by employing in vitro DNA amplification techniques, using the known sequence of the skeletal muscle receptor as reference point. The data obtained with this method indicate that the liver does not process mRNA for the skeletal muscle ryanodine receptor.
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PMID:Characterization of high-affinity ryanodine-binding sites of rat liver endoplasmic reticulum. Differences between liver and skeletal muscle. 203 82

Inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) serves as an intracellular second messenger for several neurotransmitters, hormones and growth factors by initiating calcium release from intracellular stores. A cerebellar Ins(1,4,5)P3 receptor has been characterized biochemically and shown by immunocytochemistry to be present in intracellular membranes in Purkinje cells. We show that a previously described Purkinje-cell messenger RNA encodes a protein of relative molecular mass 260,000 (260 K) with the same properties as the cerebellar Ins(1,4,5)P3 receptor. Its sequence is partially homologous to the skeletal muscle ryanodine receptor. By immunocytochemistry and electron microscopy the protein is shown to be present in all parts of the endoplasmic reticulum, including those that extend into axon terminals and dendritic spines. Our results indicate that gated calcium release from intracellular stores in muscle and Purkinje cells uses similar calcium-channel proteins localized in analogous intracellular compartments. This implies that the intracellular calcium stores in the endoplasmic reticulum of neurons extend into presynaptic terminals and dendritic spines where they may play a direct role in regulating the efficacy of neurotransmission.
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PMID:Putative receptor for inositol 1,4,5-trisphosphate similar to ryanodine receptor. 255 46

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

Ryanodine receptors (RyRs) are intracellular channels that regulate the release of Ca2+ from the endoplasmic reticulum of many cell types. The RyRs are physically associated with FK506-binding proteins (FKBPs); immunophilins, with cis-trans peptidyl-prolyl isomerase activity. FKBP12 copurifies with RyR1 (skeletal isoform) and modulates its gating. A different form of FKBP with a slightly higher molecular weight copurifies with RyR2 (cardiac isoform). Previous studies have demonstrated that FKBP stablizes gating of the skeletal Ca(2+)-release channel. In the present study, we measured the activity of cardiac RyRs incorporated into planar lipid bilayers to show that rapamycin, a drug that inhibits the prolyl isomerase activity of FKBP and dissociates FKBP from the RyR, increases the open probability and reduces the current amplitude of cardiac muscle Ca(2+)-release channels. These experiments show for the first time that submicromolar concentrations of rapamycin can alter channel function. Our results provide support for the hypotheses that FKBP functionally associates with the RyR and that the immunosuppressant drug, rapamycin, alters the function of both cardiac and skeletal muscle isoforms of the Ca(2+)-release channel. Our findings suggest that FKBP-dependent modulation of channel function may be generally applicable to all members of the intracellular Ca(2+)-release channel family and that FKBPs may play important regulatory roles in many cell processes, ranging from long-term depression in neurons to contractility in cardiomyocytes.
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PMID:Effects of rapamycin on ryanodine receptor/Ca(2+)-release channels from cardiac muscle. 863 49

The FK506 binding protein (FKBP12) is the cytosolic receptor for the immunosuppressant drugs FK506 and rapamycin. Recently, we have shown that FKBP12 copurifies with the ryanodine receptor (RyR), a 565,000-Da protein with four subunits that form the intracellular calcium release channels of the sarcoplasmic reticulum and endoplasmic reticulum. To identify the cellular function of FKBP12, in the absence of the ligands rapamycin and FK506, we coexpressed RyR and FKBP12 in insect cells. By measuring the single-channel properties of the RyR-FKBP complex reconstituted into planar lipid bilayers, we showed that FKBP12 modulates channel gating by decreasing channels with subconductance states, decreasing open probability after caffeine activation, and increasing mean open time. These effects were reversed by adding FK506 or rapamycin, both of which inhibit FKBP12 isomerase activity and dissociate the FKBP-RyR complex. These studies provided a natural cellular (ligand-independent) function for FKBP12 and established that the functional calcium release channel complex includes FKBP12. We also expressed recombinant RyR1 in Xenopus laevis oocytes that lack FKBP12. Functional studies showed that the properties of the cloned RyR1, expressed in oocytes, were comparable to those of the native RyR1. These studies showed that FKBP12 is not required for tetrameric formation of the channel structure or for insertion into an intracellular calcium-containing membrane. Both insect cells (Sf9) and Xenopus oocytes are excellent models for heterologous expression of FKBP12 and RyR. Combined with determination of the single-channel properties of the resulting complex reconstituted into planar lipid bilayers, these approaches are well suited to the study of the role of FKBP12 as a modulator of calcium channel function.
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PMID:Immunophilin Modulation of Calcium Channel Gating 881 65

Intracellular Ca2+-release channels on the sarcoplasmic reticulum of striated muscle [ryanodine receptors (RyRs)] and on the endoplasmic reticulum of almost all types of cells [inositol 1,4,5-trisphosphate receptors (IP3Rs)] comprise a unique family of molecules that are structurally and functionally distinct from all other known ion channels. These channels play crucial roles in Ca2+-mediated signaling that triggers excitation-contraction coupling, T-lymphocyte activation, fertilization, and many other cellular functions. Three forms of RyR have been identified: RyR1, expressed predominantly in skeletal muscle; RyR2, expressed predominantly in cardiac muscle; and RyR3, expressed in specialized muscles and nonmuscle tissues including the brain. RyR channels are tetramers composed of four subunits each with a molecular mass of approximately 560,000 Da. The tetrameric structures of RyR1 and RyR2 are stabilized by a channel-associated protein known as the FK506 binding protein (FKBP). FKBP is the cytosolic receptor for the immunosuppressant drugs FK506 and rapamycin that inhibit the prolyl isomerase activity of FKBP and can dissociate FKBP from RyRs. Rapamycin and FK506 increase the sensitivity of RyRs to agonists such as caffeine and could be a cause of cardiac dysfunction associated with high-dose immunosuppressant therapy by promoting leakage of Ca2+ from the sarcoplasmic reticulum. The role of prolyl isomerase activity of FKBP in regulating RyR function remains uncertain, and several models have been proposed that could explain how the channel is modulated by its association with FKBP. Three forms of IP3Rs (types 1, 2 and 3) have been characterized by cDNA cloning. Most cells have at least one form of IP3R, and many express all three types. Like RyRs, the IP3R channels are tetramers composed of four subunits (approximately 300,000 Da each). IP3R1 function is regulated by at least two major cellular signaling pathways: the second messenger IP3 activates the channel, and phosphorylation by nonreceptor protein tyrosine kinases (e.g., Fyn) increase its open probability. During end-stage human heart failure, RyR2 mRNA and protein are downregulated, whereas IP3R1 is upregulated, suggesting that altered Ca2+-release channel levels may contribute to defects in Ca2+ homeostasis. Cells that are deficient in IP3R1 exhibit defective T cell-receptor signaling and thus cannot be activated by T cell-receptor stimulation. IP3R1-deficient cells are also resistant to induced apoptosis. Thus RyRs and IP3Rs play critical roles in fundamental and diverse signaling phenomena that include excitation-contraction coupling, T-cell activation, and programmed cell death.
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PMID:Intracellular calcium-release channels: regulators of cell life and death. 912 14

Ryanodine receptors (RyRs), which form Ca2+ channels in the membrane of the endoplasmic reticulum, consist of three subtypes (RyR1, RyR2, and RyR3). The RyRs release Ca2+ from the endoplasmic reticulum into the cytoplasm and thus play an important role, especially in the contraction of skeletal and cardiac muscle cells. The genes of these RyRs are also expressed in many non-muscle tissues, but the role played by RyRs in non-muscle cells is not fully understood. In the present study, we examined the morphological changes in such cells caused by a deficiency of RyRs genes using three mutant mice lacking RyR1, RyR3, or both RyR1 and RyR3. The results showed morphological abnormalities in the adrenal cortical cells in all three mutant mice. In addition, an excessive accumulation of glycogen granules in hepatic cells, and a hypertrophy of the liver were both present in those mutant mice lacking both RyR1 and RyR3. We discuss the relationship between the morphological abnormalities of the adrenal cortex and liver induced by a deficiency of RyRs, and the possible causes of these abnormalities.
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PMID:Morphological abnormalities of adrenal gland and hypertrophy of liver in mutant mice lacking ryanodine receptors. 979 64

Malignant hyperthermia (MH) and central core disease (CCD) mutations were introduced into full-length rabbit Ca2+ release channel (RYR1) cDNA, which was then expressed transiently in HEK-293 cells. Resting Ca2+ concentrations were higher in HEK-293 cells expressing homotetrameric CCD mutant RyR1 than in cells expressing homotetrameric MH mutant RyR1. Cells expressing homotetrameric CCD or MH mutant RyR1 exhibited lower maximal peak amplitudes of caffeine-induced Ca2+ release than cells expressing wild type RyR1, suggesting that MH and CCD mutants might be "leaky." In cells expressing homotetrameric wild type or mutant RyR1, the amplitude of 10 mM caffeine-induced Ca2+ release was correlated significantly with the amplitude of carbachol- or thapsigargin-induced Ca2+ release, indicating that maximal drug-induced Ca2+ release depends on the size of the endoplasmic reticulum Ca2+ store. The content of endogenous sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2b (SERCA2b), measured by enzyme-linked immunosorbent assay, 45Ca2+ uptake, and confocal microscopy, was increased in HEK-293 cells expressing wild type or mutant RyR1, supporting the view that endoplasmic reticulum Ca2+ storage capacity is increased as a compensatory response to an enhanced Ca2+ leak. When heterotetrameric (1:1) combinations of MH/CCD mutant and wild type RyR1 were expressed together with SERCA1 to enhance Ca2+ reuptake, the amplitude of Ca2+ release in response to low concentrations of caffeine and halothane was higher than that observed in cells expressing wild type RyR1 and SERCA1. In Ca2+-free medium, MH/CCD mutants were more sensitive to caffeine than wild type RyR1, indicating that caffeine hypersensitivity observed with a variety of MH/CCD mutant RyR1 proteins is not dependent on extracellular Ca2+ concentration.
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PMID:Measurement of resting cytosolic Ca2+ concentrations and Ca2+ store size in HEK-293 cells transfected with malignant hyperthermia or central core disease mutant Ca2+ release channels. 987 4

Amyotrophic lateral sclerosis is characterized by motoneuron degeneration, in which glutamate-induced cell death is thought to play a pathogenic role. This excitotoxic process is mediated by cytosolic Ca2+ overload. The glutamatergic ionotropic channel molecules, which constitute a major route of Ca2+ entry, were present on cultured spinal motoneurons. Using ratio RT-PCR, the relative presence in isolated motoneurons of the GluR subunits of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor was evaluated. GluR1 and GluR2 mRNAs were present abundantly, while GluR3 and GluR4 mRNAs were much less abundant. The relative amount of mRNAs encoding the different protein isoforms responsible for Ca2+ uptake into the internal stores and for controlled release of Ca2+ from these stores was also determined. For the sarco/endoplasmic reticulum Ca2+ ATPases (SERCAs), only the SERCA2b class 4 splice variant was found. The inositol 1,4,5-trisphosphate receptor (IP3R) mRNAs were mainly transcribed from the IP3RI and IP3RII genes. Heterogeneity was also observed for the ryanodine receptors (RyR) as the RyR1, RyR2 and RyR3 mRNAs were present.
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PMID:Calcium handling proteins in isolated spinal motoneurons. 1057 26

Ryanodine receptors (RyR) are Ca(2+)-induced Ca(2+) release channels located on the endoplasmic reticulum, and consist of three isoforms, termed RyR1-3. We examined their expression in developing mouse brains by in situ hybridization. During the embryonic stage, RyR1 mRNA levels were highest in the rostral cortical plate, whereas RyR3 mRNA was most prominent in the caudal cortical plate and hippocampus. Initially, low levels of RyR2 mRNA were distributed in the diencephalon and brainstem. However, from postnatal day 7 onward, RyR2 mRNA became the major isoform in many brain regions, while RyR1 mRNA became prominent in the dentate gyrus and Purkinje cell layer. Postnatal down-regulation in the caudal cerebral cortex restricted RyR3 mRNA expression to the hippocampus, particularly the CA1 region. Therefore, RyR expression undergoes dynamic changes during the early postnatal period, when neurons are undergoing structural and functional differentiation.
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PMID:Developmental changes in expression of the three ryanodine receptor mRNAs in the mouse brain. 1078 7


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