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)

Ion channels have been studied extensively in ambient O2 tension (pO2), whereas tissue PO2 is much lower. The skeletal muscle calcium release channel/ryanodine receptor (RyR1) is one prominent example. Here we report that PO2 dynamically controls the redox state of 6-8 out of 50 thiols in each RyR1 subunit and thereby tunes the response to NO. At physiological pO2, nanomolar NO activates the channel by S-nitrosylating a single cysteine residue. Among sarcoplasmic reticulum proteins, S-nitrosylation is specific to RyR1 and its effect on the channel is calmodulin dependent. Neither activation nor S-nitrosylation of the channel occurs at ambient PO2. The demonstration that channel cysteine residues subserve coupled O2 sensor and NO regulatory functions and that these operate through the prototypic allosteric effector calmodulin may have general implications for the regulation of redox-related systems.
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PMID:The skeletal muscle calcium release channel: coupled O2 sensor and NO signaling functions. 1096 11

In the renal collecting duct, vasopressin increases osmotic water permeability (P(f)) by triggering trafficking of aquaporin-2 vesicles to the apical plasma membrane. We investigated the role of vasopressin-induced intracellular Ca(2+) mobilization in this process. In isolated inner medullary collecting ducts (IMCDs), vasopressin (0.1 nm) and 8-(4-chlorophenylthio)-cAMP (0.1 mm) elicited marked increases in [Ca(2+)](i) (fluo-4). Vasopressin-induced Ca(2+) mobilization was completely blocked by preloading with the Ca(2+) chelator BAPTA. In parallel experiments, BAPTA completely blocked the vasopressin-induced increase in P(f) without affecting adenosine 3',5'-cyclic monophosphate (cAMP) production. Previously, we demonstrated the lack of activation of the phosphoinositide-signaling pathway by vasopressin in IMCD, suggesting an inositol 1,4,5-trisphosphate-independent mechanism of Ca(2+) release. Evidence for expression of the type 1 ryanodine receptor (RyR1) in IMCD was obtained by immunofluorescence, immunoblotting, and reverse transcription-polymerase chain reaction. Ryanodine (100 microm), a ryanodine receptor antagonist, blocked the arginine vasopressin-mediated increase in P(f) and blocked vasopressin-stimulated redistribution of aquaporin-2 to the plasma membrane domain in primary cultures of IMCD cells, as assessed by immunofluorescence immunocytochemistry. Calmodulin inhibitors (W7 and trifluoperazine) blocked the P(f) response to vasopressin and the vasopressin-stimulated redistribution of aquaporin-2. The results suggest that Ca(2+) release from ryanodine-sensitive stores plays an essential role in vasopressin-mediated aquaporin-2 trafficking via a calmodulin-dependent mechanism.
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PMID:Regulation of aquaporin-2 trafficking by vasopressin in the renal collecting duct. Roles of ryanodine-sensitive Ca2+ stores and calmodulin. 1097 64

A negatively charged region of the N-terminal portion of the skeletal ryanodine receptor (RyR), located between residues 1872-1923, is involved in Ca (2+)-dependent regulation of the Ca(2+)-release channel. This region is divergent between the skeletal (RyR1) and cardiac (RyR2) isoforms of the channel, and is known as D3. Ca(2+) exerts important regulatory functions on the RyR, being involved in both activation and inactivation functions of the channel, i.e. the effects occurring at micromolar and millimolar Ca(2+) concentrations respectively. To characterize the role of D3 in the Ca(2+)-dependent regulation of the Ca(2+)-release channel, we studied the functional consequences of deleting the D3 region from RyR1 (DeltaD3-RyR1) using a heterologous expression system, [(3)H]ryanodine binding assays and single-channel recordings in lipid bilayers. Deletion of the D3 region selectively affected Ca(2+)-dependent regulation of RyR1, but did not alter [(3)H]ryanodine binding or the effect of other modulators on the RyR. Compared with full-length RyR1 (wt-RyR1), the Ca(2+)-dependence curve of DeltaD3-RyR1 is broader, reflecting increased sensitivity to Ca(2+) activation and decreased sensitivity to Ca(2+) inactivation. In addition, DeltaD3-RyR1 was more resistant to inhibition by Mg(2+). Comparison of the effect of caffeine on wt-RyR1 and DeltaD3-RyR1 suggested that D3 is an important region of RyR that participates in Ca(2+)-dependent activation and inactivation of the Ca(2+)-release channel.
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PMID:Characterization of a calcium-regulation domain of the skeletal-muscle ryanodine receptor. 1099 47

Regulation of cytosolic Ca(2+) is important for a variety of cell functions. The ryanodine receptor (RyR) is a Ca(2+) channel that conducts Ca(2+) from internal pools to the cytoplasm. To demonstrate the presence of the RyR in the pancreatic acinar cell, we performed reverse transcriptase (RT)-PCR, Western blot, immunocytochemistry and microscopic Ca(2+)-release measurements on these cells. RT-PCR showed the presence of mRNA for RyR isoforms 1, 2 and 3 in both rat pancreas and dispersed pancreatic acini. Furthermore, mRNA expression for RyR isoforms 1 and 2 was demonstrated by RT-PCR in individual pancreatic acinar cells selected under the microscope. Western-blot analysis of acinar cell immunoprecipitates, using antibodies against RyR1 and RyR2, showed a high-molecular-mass (>250 kDa) protein band that was much less intense when immunoprecipitated in the presence of RyR peptide. Functionally, permeablized acinar cells stimulated with the RyR activator, palmitoyl-CoA, released Ca(2+) from both basolateral and apical regions. These data show that pancreatic acinar cells express multiple isoforms of the RyR and that there are functional receptors throughout the cell.
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PMID:Multiple isoforms of the ryanodine receptor are expressed in rat pancreatic acinar cells. 1099 70

We examined the effect of low concentrations of H(2)O(2) on the Ca(2+)-release channel/ryanodine receptor (RyR) to determine if H(2)O(2) plays a physiological role in skeletal muscle function. Sarcoplasmic reticulum vesicles from frog skeletal muscle and type 1 RyRs (RyR1) purified from rabbit skeletal muscle were incorporated into lipid bilayers. Channel activity of the frog RyR was not affected by application of 4.4 mM (0.02%) ethanol. Open probability (P(o)) of such ethanol-treated RyR channels was markedly increased on subsequent addition of 10 microM H(2)O(2). Increase of H(2)O(2) to 100 microM caused a further increase in channel activity. Application of 4.4 mM ethanol to 10 microM H(2)O(2)-treated RyRs activated channel activity. Exposure to 10 or 100 microM H(2)O(2) alone, however, failed to increase P(o). Synergistic action of ethanol and H(2)O(2) was also observed on the purified RyR1 channel, which was free from FK506 binding protein (FKBP12). H(2)O(2) at 100-500 microM had no effect on purified channel activity. Application of FKBP12 to the purified RyR1 drastically decreased channel activity but did not alter the effects of ethanol and H(2)O(2). These results suggest that H(2)O(2) may play a pathophysiological, but probably not a physiological, role by directly acting on skeletal muscle RyRs in the presence of ethanol.
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PMID:H(2)O(2) and ethanol act synergistically to gate ryanodine receptor/calcium-release channel. 1102 84

Since the role of sarcoplasmic reticulum (SR) in the E-C coupling of mammalian atrial cells has long been a subject of debate, biochemical, electrophysiological and immunological assays were performed in order to define and compare the properties of the Ca(2+)-release channel-ryanodine receptor (RyR)-from atrial and ventricular tissues. Cardiac SR preparations from human, canine and ovine tissues were compared using [(3)H]ryanodine binding, channel reconstitution into planar lipid bilayers and Western blot analysis involving RyR antibodies. [(3)H]ryanodine binding assays revealed a K(d)value of; 2.5 n M for all investigated cardiac tissues. Bound [(3)H]ryanodine was Ca(2+)-dependent with similar EC(50)values of 0.43, 0.49 and 0.79 microM for human atrium, canine ventricle and ovine atrium, respectively. However the density of binding sites was 4.5 times lower in atrial than in ventricular tissues. Beyond the presence of selective K(+)channels (gamma=188 pS) recorded in the SR enriched fraction of human atrium, the activity of a large conducting (gamma=671 pS) cationic channel was also observed. The latter displayed typical characteristics of Ca(2+)-release channels which were activated by 10 microM free [Ca(2+)] and 2 m M ATP. Western blot analysis revealed the presence of the RyR2 isoform in atrial and ventricular samples whereas no immunoreactivity was detected with specific RyR1 and RyR3 antibodies. Our results, obtained at the molecular level, are consistent with the presence of functional SR in human atrial cells. The human atrial Ca(2+)-release channel displays binding and regulating properties typical of the RyR2 isoform.
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PMID:Characterization of the sarcoplasmic reticulum k(+) and Ca(2+)-release channel-ryanodine receptor-in human atrial cells. 1104 Jan 8

Of the three known ryanodine receptor (RyR) isoforms expressed in muscle, RyR1 and RyR2 have well-defined roles in contraction. However, studies on mammalian RyR3 have been difficult because of low expression levels relative to RyR1 or RyR2. Using the herpes simplex virus 1 (HSV-1) helper-free amplicon system, we expressed either RyR1 or RyR3 in 1B5 RyR-deficient myotubes. Western blot analysis revealed that RyR1- or RyR3-transduced cells expressed the appropriate RyR isoform of the correct molecular mass. Although RyR1 channels exhibited the expected unitary conductance for Cs(+) in bilayer lipid membranes, 74 of 88 RyR3 channels exhibited pronounced subconductance behavior. Western blot analysis with an FKBP12/12.6-selective antibody reveals that differences in gating behavior exhibited by RyR1 and RyR3 may be, in part, the result of lower affinity of RyR3 for FKBP12. In calcium imaging studies, RyR1 restored skeletal-type excitation-contraction coupling, whereas RyR3 did not. Although RyR3-expressing myotubes were more sensitive to caffeine than those expressing RyR1, they were much less sensitive to 4-chloro-m-cresol (CMC). In RyR1-expressing cells, regenerative calcium oscillations were observed in response to caffeine and CMC but were never seen in RyR3-expressing 1B5 cells. In [(3)H]ryanodine binding studies, only RyR1 exhibited sensitivity to CMC, but both RyR isoforms responded to caffeine. These functional differences between RyR1 and RyR3 expressed in a mammalian muscle context may reflect differences in association with accessory proteins, especially FKBP12, as well as structural differences in modulator binding sites.
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PMID:Divergent functional properties of ryanodine receptor types 1 and 3 expressed in a myogenic cell line. 1105 26

Ca(2+)-release from the sarcoplasmic or endoplasmic reticulum, the intracellular Ca(2+) store, is mediated by the ryanodine receptor (RyR) and/or the inositol trisphosphate receptor (IP3R). While IP3R is a ligand(IP3)-operated channel, RyR can be gated by a ligand (Ca(2+)) and/or mechanical coupling with the voltage sensor. There are three genetically distinct isoforms among RyR in mammals: RyR1-3. RyR1, the primary isoform in the skeletal muscle, can be gated by direct or indirect coupling with the conformation change of the alpha 1S subunit of dihydropyridine receptor (DHPR) on the T-tubules (transversely invaginated sarcolemma) upon depolarization of skeletal muscles or by the increased cytoplasmic Ca(2+) (Ca(2+)-induced Ca(2+) release, CICR). RyR2, the primary isoform in the cardiac ventricular muscle (and, in a lesser amount, the brain), can be gated by Ca(2+) which flows in through DHPR, especially the alpha1C subunit on depolarization. RyR3 is distributed ubiquitously in various tissues and may be coexpressed with RyR1 and RyR2. RyR3 is considered to be similar to RyR2 in the respect that it can be activated by Ca(2+), in view of the lack of available evidence to show the activation by the alpha1S subunit. Therefore, it is anticipated that RyR3 might take part through CICR in Ca(2+) signaling in smooth muscle and other non-muscle cells. To address the possible involvement of the CICR mechanism in the Ca(2+) signal transduction, it is critical to assess the effect of Mg(2+) on the CICR activity and the cytoplasmic concentration of Mg(2+). In this brief review, our discussion focuses on the effects of Ca(2+) and Mg(2+) on the activity of RyR3.
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PMID:Putative roles of type 3 ryanodine receptor isoforms (RyR3). 1115 Jul 32

Arrhythmogenic right ventricular dysplasia type 2 (ARVD2, OMIM 600996) is an autosomal dominant cardiomyopathy, characterized by partial degeneration of the myocardium of the right ventricle, electrical instability and sudden death. The disease locus was mapped to chromosome 1q42--q43. We report here on the physical mapping of the critical ARVD2 region, exclusion of two candidate genes (actinin 2 and nidogen), elucidation of the genomic structure of the cardiac ryanodine receptor gene (RYR2) and identification of RYR2 mutations in four independent families. In myocardial cells, the RyR2 protein, activated by Ca(2+), induces the release of calcium from the sarcoplasmic reticulum into the cytosol. RyR2 is the cardiac counterpart of RyR1, the skeletal muscle ryanodine receptor, involved in malignant hyperthermia (MH) susceptibility and in central core disease (CCD). The RyR2 mutations detected in the present study occurred in two highly conserved regions, strictly corresponding to those where mutations causing MH or CCD are clustered in the RYR1 gene. The detection of RyR2 mutations causing ARVD2, reported in this paper, opens the way to pre-symptomatic detection of carriers of the disease in childhood, thus enabling early monitoring and treatment.
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PMID:Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). 1115 36

Polycyclic aromatic hydrocarbons are environmental pollutants known to be carcinogenic and immunotoxic. In intact cell assays, benzo[a]pyrene (B[a]P) disrupts Ca(2+) homeostasis in both immune and nonimmune cells, but the molecular mechanism is undefined. In this study, B[a]P and five metabolites are examined for their ability to alter Ca(2+) transport across microsomal membranes. Using a well-defined model system, junctional SR vesicles from skeletal muscle, we show that a single o-quinone metabolite of B[a]P, B[a]P-7,8-dione, can account for altered Ca(2+) transport across microsomal membranes. B[a]P-7,8-dione induces net Ca(2+) release from actively loaded vesicles in a dose-, time-, and Ca(2+)-dependent manner. In the presence of 5 microM extravesicular Ca(2+), B[a]P-7,8-dione exhibited threshold and EC(50) values of 0.4 and 2 microM, respectively, and a maximal release rate of 2 micromol of Ca(2+) min(-1) mg(-1). The mechanism by which B[a]P-7,8-dione enhanced Ca(2+) efflux was further investigated by measuring macroscopic fluxes and single RyR1 channels reconstituted in bilayer lipid membranes and direct measurements of SERCA catalytic activity. B[a]P-7,8-dione (< or = 20 microM) had no measurable effect on initial rates of Ca(2+) accumulation in the presence of ruthenium red to block ryanodine receptor (RyR1), nor did it alter Ca(2+)-dependent (thapsigargin-sensitive) ATPase activity. B[a]P-7,8-dione selectively altered the function of RyR1 in a time-dependent diphasic manner, first activating then inhibiting channel activity. Considering that RyR1 and its two alternate isoforms are broadly expressed in mammalian cells and their important role in Ca(2+)-signaling, the present results reveal a mechanism by which metabolic bioactivation of B[a]P may mediate RyR dysfunction of pathophysiological significance.
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PMID:A bioactive metabolite of benzo[a]pyrene, benzo[a]pyrene-7,8-dione, selectively alters microsomal Ca2+ transport and ryanodine receptor function. 1117 46


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