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)

The distributions of ryanodine receptor-like immunoreactivity and Ca-ATPase-like immunoreactivity were identified in the guinea-pig and rat central nervous system using antibodies raised against the rabbit skeletal muscle ryanodine receptor and Ca-ATPase. In both guinea-pig and rat cerebellum, the ryanodine receptor-like immunoreactivity was restricted to the soma and dendrites of Purkinje cells. In the medulla, neuron somata in the hypoglossal nucleus were stained in both species, but in the dorsal motor nucleus of the vagus somata were stained in guinea-pigs but not in rats. This species difference in ryanodine receptor-like immunoreactivity is consistent with the species difference in expression of a ryanodine sensitive, calcium activated potassium conductance in neurons of the dorsal motor nucleus of the vagus. Immunoreactivity to Ca-ATPase was present in vagal motoneurons in both species with denser staining in the guinea-pig. The data further support the idea that, in neurons of the dorsal motor nucleus of the vagus, release of intracellular calcium stores via a ryanodine receptor activates a specific class of potassium channels, thereby modulating cell excitability.
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PMID:Distribution of ryanodine receptor-like immunoreactivity in mammalian central nervous system is consistent with its role in calcium-induced calcium release. 839 Jun 24

Two novel natural ryanoids from extracts of the wood of Ryania speciosa Vahl were evaluated with sarcoplasmic reticulum (SR) vesicles for their binding affinities and their activating and deactivating effects on Ca2+ release channels. The new ryanoids, which are more polar than the known Ryania constituents ryanodine and didehydro-(9,21)-ryanodine, were purified using silica gel column chromatography and reverse phase high performance liquid chromatography. The new ryanoids were designated ester E and ester F, in keeping with nomenclature previously used in the literature. These compounds were identified by NMR spectroscopy and mass spectroscopy as C9ax-hydroxyryanodine and C8ax-hydroxy-C10-epi-dehydroryanodine, respectively. Binding of esters E and F to the high affinity (nanomolar Kd) site on SR Ca2+ release channels was determined from relative binding affinity assays using 6.7 nM [3H]ryanodine. Apparent Kd values of ryanodine, ester E, and ester F for binding to this domain on the skeletal muscle ryanodine receptor/SR Ca2+ release channel were 4.4 +/- 0.8, 65 +/- 10, and 257 +/- 53 nM, respectively (mean +/- standard deviation, four or more experiments). Apparent Kd values for cardiac muscle receptors were 0.51 +/- 0.01, 12 +/- 0.4, and 57 nM, respectively. As a functional indication of the effects of the ryanoids, channel-opening (activator) and channel-closing (deactivator) actions were assessed from the ability of the ryanoids to alter the rate of Ca2+ efflux from passively loaded skeletal muscle junctional sarcoplasmic reticular vesicles (JSRV). Activator actions among the ryanoids were similar, in that they exhibited apparently parallel concentration-effect curves, having a slope of 40% Ca2+ loss/decade increment in ryanoid concentration. Half-maximal values for activation (EC50 values) were 2.5, 63, and 43 microM for ryanodine, ester E, and ester F, respectively. Maximal channel opening by ester E was significantly less than that produced by the other ryanoids. The deactivator actions of the compounds on skeletal JSRV were dissimilar, in that their concentration-effect curves appeared not to be parallel. The quotient of the EC50 for deactivation and that for activation was taken as the concentration-coupling ratio (CCR). The CCR for ryanodine was 114 and that for ester F was 72, but the CCR for ester E was only 21. ATP-dependent Ca2+ accumulation by cardiac JSRV provided a second means to evaluate deactivator actions of the ryanoids. Results from cardiac JSRV assays were in general similar to those from skeletal JSRV assays.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Differential activating and deactivating effects of natural ryanodine congeners on the calcium release channel of sarcoplasmic reticulum: evidence for separation of effects at functionally distinct sites. 839 96

Porcine skeletal and cardiac muscle sarcoplasmic reticulum (SR) vesicle fractions enriched in the ryanodine receptor were phosphorylated in the presence of [gamma-32P]MgATP and either exogenous cAMP-dependent protein kinase (cAMP-PK), or Ca2+ plus calmodulin. Phosphorylation of the cardiac muscle ryanodine receptor in the presence of either cAMP-PK or calmodulin (6.4 and 10.6 pmol Pi/mg SR respectively) was approximately equal to or twice the [3H]ryanodine binding activity of this preparation (5.2 pmol/mg). Furthermore, cardiac muscle ryanodine receptor Pi incorporation catalyzed by cAMP-PK and calmodulin was approximately additive. In skeletal muscle SR, however, the level of cAMP-PK or calmodulin catalyzed phosphorylation of the intact ryanodine receptor (0.2 or 2.9 pmol Pi/mg SR, respectively) was much less than the [3H]ryanodine binding activity of this fraction (11.6 pmol/mg). Furthermore, Pi incorporation into the intact skeletal muscle ryanodine receptor was 3-8-fold less than that incorporated into a component of slightly lower M(r). Although this latter component comigrated with an immunoreactive fragment of the ryanodine receptor on polyacrylamide gels, it did not appear to be derived from the ryanodine receptor. We conclude that the significant phosphorylation of the cardiac muscle SR ryanodine receptor indicates a likely physiological role for protein kinase-mediated regulation of this Ca(2+)-channel. In contrast, the minimal phosphorylation of the skeletal muscle SR ryanodine receptor indicates that such a role of protein kinases is unlikely in this tissue.
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PMID:Phosphorylation of the porcine skeletal and cardiac muscle sarcoplasmic reticulum ryanodine receptor. 843 48

Two structurally related forms of intracellular calcium release channels that can mediate the release of intracellular calcium have been identified: the ryanodine receptors (RyR) and the inositol 1,4,5-trisphosphate receptors (IP3R). Each channel responds to distinct pathways for activation. The IP3R is activated by IP3 and the RyR is thought to be activated by calcium or by another second messenger cADP ribose. It has been proposed that each type of channel subserves a specialized pool of intracellular calcium, and it is not understood why some cell types require more than one form of intracellular calcium release channel. The present study was designed to examine whether the RyR can substitute for the IP3R during oocyte maturation. IP3R expression was inhibited in Xenopus laevis oocytes using antisense oligonucleotides. These oocytes, with reduced levels of IP3R, demonstrated a marked delay in the time course of progesterone-induced maturation. The cloned skeletal muscle RyR1 was then expressed in X. laevis oocytes that were deficient in IP3R. Functional studies showed that the properties of the cloned RyR1, expressed in oocytes, were comparable to those of the native RyR1. X. laevis oocytes deficient in IP3R, but expressing RyR1, were able to undergo progesterone-induced maturation with a time course comparable to that seen in wild-type oocytes when caffeine was used to activate RyR and induce intracellular calcium release. These studies show that RyR1 can substitute for the IP3R as the intracellular calcium release channel required for Xenopus oocyte maturation and that intracellular calcium release is important for controlling the rate of progesterone-induced maturation.
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PMID:Expressed ryanodine receptor can substitute for the inositol 1,4,5-trisphosphate receptor in Xenopus laevis oocytes during progesterone-induced maturation. 861 69

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

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

Single-channel recordings have indicated that ryanodine receptor (RyR1) mutation Arg615Cys of porcine malignant hyperthermia-susceptible (MHS) muscle is not directly associated with the enhanced caffeine sensitivity of MH(S) muscle [1]. In the present study, the effect of a novel activator of RyR1, 4-chlorom-cresol (4-CmC), was investigated on high-affinity [3H]ryanodine binding to porcine skeletal sarcoplasmic reticulum. The 4-CmC affinity of [3H]ryanodine binding to MHS vesicles was 2-fold higher compared to that in normal tissue. This enhanced affinity was confirmed when the effect of 4-CmC on [3H]ryanodine binding to the isolated CHAPS-solubilized MHS RyR1 was investigated. 4-CmC is, therefore, suggested to be a potent tool to distinguish between Ca2+ release from MHS and normal muscle.
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PMID:4-Chloro-m-cresol: a specific tool to distinguish between malignant hyperthermia-susceptible and normal muscle. 867 99

A fusion protein encompassing Gly341 of the skeletal muscle ryanodine receptor was used to raise monoclonal antibodies; epitope mapping demonstrates that monoclonal antibody 419 (mAb419) reacts with a sequence a few residues upstream from Gly341. The mAb419 was then used to probe ryanodine receptor (RYR) functions. Our results show that upon incubation of triads vesicles with mAb419 the Ca2+-induced Ca2+ release rate at pCa 8 was increased. Equilibrium evaluation of [3H]ryanodine binding at different [Ca2+] indicates that mAb419 shifted the half-maximal [Ca2+] for stimulation of ryanodine binding to lower value (0.1 versus 1.2 microM). Such functional effects may be due to a direct action of the Ab on the Ca2+ binding domain of the RYR or to the perturbation by the Ab of the intramolecular interaction between the immunopositive region and regulatory domain of the RYR. The latter hypothesis was tested directly using the optical biosensor BIAcore (Pharmacia Biotech Inc.): we show that the immunopositive RYR polypeptide is able to interact with the native RYR complex. Ligand overlays with immunopositive digoxigenin-RYR fusion protein indicate that such an interaction might occur with a calmodulin binding domain (defined by residues 3010-3225) and with a polypeptide defined by residues 799-1172. In conclusion our results suggest that the stimulation by the mAb419 of the RYR channel activity is due to the perturbation of an intramolecular interaction between the immunopositive polypeptide and a Ca2+ regulatory site probably corresponding to a calmodulin binding domain.
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PMID:Role of malignant hyperthermia domain in the regulation of Ca2+ release channel (ryanodine receptor) of skeletal muscle sarcoplasmic reticulum. 879 51

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

The skeletal muscle ryanodine receptor (RYR1) belongs to a family of calcium release channels that are expressed in different tissues. The RYR1 gene is one of the largest genes characterized, so far, containing a 15253 nucleotide ORF in swine. To study the genomic organization of the porcine skeletal muscle ryanodine receptor gene we have isolated seven genomic fragments spanning 72.7 kb of chromosomal DNA of chromosome 6q12. This region harbours exons 1 to 71 coding for 3538 amino acids (69.6%) of the ryanodine receptor 1.
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PMID:The porcine skeletal muscle ryanodine receptor gene structure coding region 1 to 10614 harbouring 71 exons. 893 69


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