Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 skeletal muscle, an anterograde signal from the dihydropyridine receptor (DHPR) to the ryanodine receptor (RyR1) is required for excitation-contraction (EC) coupling and a retrograde signal from RyR1 to the DHPR regulates the magnitude of the calcium current carried by the DHPR. As a tool for studying biosynthesis and targeting, we constructed a cDNA encoding green fluorescent protein (GFP) fused to the amino terminal of RyR1 and expressed it in dyspedic myotubes. The GFP-RyR1 was present in a restricted domain near the nucleus injected with cDNA and was fully functional, which places constraints on the location of the amino terminal in the folded structure of RyR1.
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PMID:Structure and targeting of RyR1: implications from fusion of green fluorescent protein at the amino-terminal. 1136 Nov 29

In striated muscles, excitation-contraction coupling is mediated by the functional interplay between dihydropyridine receptor L-type calcium channels (DHPR) and ryanodine receptor calcium-release channel (RyR). Although significantly different molecular mechanisms are involved in skeletal and cardiac muscles, bidirectional cross-talk between the two channels has been described in both tissues. In the present study using surface plasmon resonance spectroscopy, we demonstrate that both RyR1 and RyR2 can bind to structural elements of the C-terminal cytoplasmic domain of alpha(1C). The interaction is restricted to the CB and IQ motifs involved in the calmodulin-mediated Ca(2+)-dependent inactivation of the DHPR, suggesting functional interactions between the two channels.
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PMID:Skeletal and cardiac ryanodine receptors bind to the Ca(2+)-sensor region of dihydropyridine receptor alpha(1C) subunit. 1157 44

Both in vivo and in vitro studies suggest that the Glu(724)-Pro(760) (peptide C) region of the dihydropyridine receptor alpha1 II-III loop is important for excitation-contraction coupling, although its actual function has not yet been elucidated. According to our recent studies, peptide C inhibits Ca(2+) release induced by T-tubule depolarization or peptide A. Here we report that peptide C has Ca(2+)-dependent dual functions on the skeletal muscle ryanodine receptor. Thus, at above-threshold [Ca(2+)]s (> or =0.1 microm) peptide C blocked peptide A-induced activation of the ryanodine receptor (ryanodine binding and Ca(2+) release); peptide C also blocked T-tubule depolarization-induced Ca(2+) release. However, at sub-threshold [Ca(2+)]s (<0.1 microm), peptide C enhanced ryanodine binding and induced Ca(2+) release. If peptide A was present, together with peptide C, both peptides produced additive activation effects. Neither peptide A nor peptide C produced any appreciable effect on the cardiac muscle ryanodine receptor at both high (1.0 microm) and low (0.01 microm) Ca(2+) concentrations. These results suggest the possibility that the in vivo counterpart of peptide C retains both activating and blocking functions of the skeletal muscle-type excitation-contraction coupling.
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PMID:Ca2+-dependent dual functions of peptide C. The peptide corresponding to the Glu724-Pro760 region (the so-called determinant of excitation-contraction coupling) of the dihydropyridine receptor alpha 1 subunit II-III loop. 1168 72

Calmodulin (CaM) binds to the ryanodine receptor/calcium release channel of skeletal muscle (RyR1), both in the absence and presence of Ca(2+), and regulates the activity of the channel activity by activating and inhibiting it, respectively. Using cryo-electron microscopy and three-dimensional reconstruction, we found that one apoCaM binds per RyR1 subunit along the sides of the cytoplasmic assembly of the receptor. This location is distinct from but close to the location found for Ca(2+)-CaM, providing a structural basis for efficient switching of CaM between these two positions with the oscillating intracellular Ca(2+) concentration that generates muscle relaxation/contraction cycles. The locations of apoCaM and Ca(2+)-CaM at a critical region for RYR1-dihydropyridine receptor interaction are suggestive of a direct role for CaM in the mechanism of excitation-contraction coupling.
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PMID:Apocalmodulin and Ca2+-calmodulin bind to neighboring locations on the ryanodine receptor. 1169 36

In skeletal muscle, excitation-contraction (EC) coupling and retrograde signaling are thought to result from direct interactions between the ryanodine receptor (RyR1) and the alpha(1) subunit of the dihydropyridine receptor (alpha(1S)). Previous work has shown that the s53 region of alpha(1S) (residues 720-765 in the II-III loop) and regions R10 (1635-2636) and R9 (2659-3720) of RyR1 are involved in this signaling. Using the yeast two-hybrid system, we here report an interaction between s53 and the sR16 region of RyR1 (1837-2168, within R10), whereas no interaction was seen using upstream residues of the alpha(1S) II-III loop (s31, 666-709). The specificity of the s53-sR16 interaction was tested by using fragments of the cardiac RyR (RyR2) and DHPR (alpha(1C)) that correspond to sR16 and s53, respectively. No interaction was observed for sR16 x c53 (alpha(1C) 850-897), but weak interaction was occasionally observed for s53 x cR16 (RyR2 1817-2142). To test the functional significance of the s53 x sR16 interaction, we expressed in dyspedic myotubes a chimeric RyR (chimeraR16) in which sR16 was substituted for the corresponding region of RyR2. ChimeraR16 was found to mediate weak skeletal-type EC coupling. To test the necessity of sR16 sequence for coupling, we used "chimeraR16-rev," in which sR16 and a small upstream region of RyR1 were replaced by RyR2 sequence. ChimeraR16-rev did not differ from RyR1 in its ability to mediate EC coupling. Thus, interaction between residues 720-765 of alpha(1S) and residues 1837-2168 of RyR1 appears to contribute to but is not essential for EC coupling in skeletal muscle.
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PMID:Identification of a region of RyR1 that participates in allosteric coupling with the alpha(1S) (Ca(V)1.1) II-III loop. 1172 51

In skeletal muscle, excitation-contraction coupling involves a functional interaction between the ryanodine receptor (RyR) and the dihydropyridine receptor (DHPR). The domain corresponding to Thr(671)-Leu(690) of the II-III loop of the skeletal DHPR alpha(1)-subunit is able to regulate RyR properties and calcium release from sarcoplasmic reticulum, whereas the domain corresponding to Glu(724)-Pro(760) antagonizes this effect. Two peptides, covering these sequences (peptide A(Sk) and C(Sk), respectively) were immobilized on polystyrene beads. We demonstrate that peptide A(Sk) binds to the skeletal isoform of RyR (RyR1) whereas peptide C(Sk) does not. Using surface plasmon resonance detection, we show that 1) domain Thr(671)-Leu(690) is the only sequence of the II-III loop binding with RyR1 and 2) the interaction of peptide A(Sk) with RyR1 is not modulated by Ca(2+) (pCa 9-2) nor by Mg(2+) (up to 10 mM). In contrast, this interaction is strongly potentiated by the immunophilin FKBP12 (EC(50) = 10 nM) and inhibited by both rapamycin (IC(50) = 5 nM) and FK506. Peptide A(Sk) induces a 300% increase of the opening probability of the RyR1 incorporated in lipid bilayer. Removal of FKBP12 from RyR1 completely abolishes this effect of domain A(Sk) on RyR1 channel behavior. These results demonstrate a direct interaction of the RyR1 with the discrete domain of skeletal DHPR alpha(1)-subunit corresponding to Thr(671)-Leu(690) and show that the association of FKBP12 with RyR1 specifically modulates this interaction.
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PMID:FKBP12 modulation of the binding of the skeletal ryanodine receptor onto the II-III loop of the dihydropyridine receptor. 1175 3

A key event in skeletal muscle activation is the rapid release of Ca(2+) from the sarcoplasmic reticulum (SR), the Ca(2+) storage organelle in the muscle cell. The surface membrane/transverse tubules and the SR form functional units (calcium release units containing one or two couplons or junctions), where the voltage-sensing dihydropyridine receptor of the surface membrane interacts with the SR Ca(2+) release channel [ryanodine receptor (RyR)] and depolarization of the cell membrane is converted into Ca(2+) release from the SR. Although RyR1 is the most important isoform in skeletal muscle, some muscles also express high levels of RyR3, an isoform with a wide tissue distribution. The cytoplasmic domains of RyRs are visible in the electron microscope as periodically disposed feet. We find that, in muscles containing only RyR1, feet are exclusively located over the junctional SR surface facing the surface membrane/transverse tubule. In muscles containing RyR1 as well as RyR3, additional feet are located in lateral parajunctional regions immediately adjacent to junctional SR. Biochemical content of RyR3 and content of parajunctional feet are highly correlated in different muscles and the disposition of parajunctional versus junctional feet are notably different. On the basis of these two observations, we postulate that RyR3s are restricted to the parajunctional region, and thus their activation must be indirect and derivative during excitation-contraction coupling.
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PMID:Type 3 ryanodine receptors of skeletal muscle are segregated in a parajunctional position. 1181 57

Most adult mammalian skeletal muscles contain only one isoform of ryanodine receptor (RyR1), whereas neonatal muscles contain two isoforms (RyR1 and RyR3). Membrane depolarization fails to evoke calcium release in muscle cells lacking RyR1, demonstrating an essential role for this isoform in excitation-contraction coupling. In contrast, the role of RyR3 is unknown. We studied the participation of RyR3 in calcium release in wild type (containing both RyR1 and RyR3 isoforms) and RyR3-/- (containing only RyR1) myotubes in the presence or absence of imperatoxin A (IpTxa), a high-affinity agonist of ryanodine receptors. IpTxa significantly increased the amplitude and the rate of release only in wild-type myotubes. Calcium currents, recorded simultaneously with the transients, were not altered with IpTxa treatment. [(3)H]ryanodine binding to RyR1 or RyR3 was significantly increased in the presence of IpTxa. Additionally, IpTxa modified the gating and conductance level of single RyR1 or RyR3 channels when studied in lipid bilayers. Our data show that IpTxa can interact with both RyRs and that RyR3 is functional in myotubes and it can amplify the calcium release signal initiated by RyR1, perhaps through a calcium-induced mechanism. In addition, our data indicate that when RyR3-/- myotubes are voltage-clamped, the effect of IpTxa is not detected because RyR1s are under the control of the dihydropyridine receptor.
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PMID:Imperatoxin a enhances Ca(2+) release in developing skeletal muscle containing ryanodine receptor type 3. 1186 48

Muscle excitation-contraction coupling is, in large part, regulated by the activity of two proteins. These are the ryanodine receptor (RyR), which is an intracellular Ca2+ release channel and the dihydropyridine receptor (DHPR), which is a voltage gated L-type calcium channel. In skeletal muscle, the physical association between RyR1 and L-type Ca2+ channels is required for muscle excitation-contraction coupling. RyRs also regulate intracellular Ca2+ homeostasis, thereby contributing to a variety of cellular functions in different tissues. A wide variety of modulators directly regulate RyR1 activity and, consequentially, alter both excitation-contraction coupling and calcium homeostasis. Calmodulin, one of these cellular modulators, is a ubiquitously expressed 17 kDa Ca2+ binding protein containing four E-F hands, which binds to RyR1 at both nanomolar and micromolar Ca2+ concentrations. Apocalmodulin (Ca2+ free calmodulin) is a partial agonist, while Ca2+calmodulin is an inhibitor of RyR1. This conversion of calmodulin from an activator to an inhibitor is due to Ca2+ binding to the two C-terminal sites on calmodulin. Calmodulin can also modulate the L-type Ca2+ channel in the transverse tubule membrane, producing either inactivation or facilitation of the channel upon elevation of the local Ca2+ concentrations. Calmodulin binds to a region on RyR1 corresponding to amino acids 3614-3643 and to a region in the carboxy-terminal tail of the L-type Ca2+ channel (1 subunit. However, these calmodulin binding motifs on both proteins bind to undetermined motifs on the other protein, suggesting that they represent more general protein-protein interaction motifs. These findings raise questions about the role of calmodulin in excitation-contraction coupling in skeletal muscle.
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PMID:Calmodulin modulation of proteins involved in excitation-contraction coupling. 1204 19

Functional and molecular biological evidence exists for the expression of ryanodine receptors in non-muscle cells. In the present study, RT-PCR and 5'-rapid amplification of cDNA 5'-end (5'-RACE analysis) provided evidence for the presence of a type 1 ryanodine receptor/Ca2+ channel (RyR1) in diverse cell types. In parotid gland-derived 3-9 (epithelial) cells, the 3'-end 1589 nucleotide sequence for a rat RyR shared 99% homology with rat brain RyR1. Expression of this RyR mRNA sequence in exocrine acinar cells, endocrine cells, and liver in addition to skeletal muscle and cardiac muscle, suggests wide tissue distribution of the RyR1. Positive identification of a 5'-end sequence was made for RyR1 mRNA in rat skeletal muscle and brain, but not in parotid cells, pancreatic islets, insulinoma cells, or liver. These data suggest that a modified RyR1 is present in exocrine and endocrine cells, and liver. Western blot analysis showed L-type Ca2+ channel-related proteins in parotid acinar cells, which were of comparable size to those identified in skeletal and cardiac muscle, and in brain. Immunocytochemistry carried out on intact parotid acini demonstrated that the dihydropyridine receptor was preferentially co-localized with the IP3 receptor in the apical membranes. From these data we conclude that certain non-muscle cells express a modified RyR1 and L-type Ca2+ channel proteins. These receptor/channels may play a role in Ca2+ signaling involving store-operated Ca2+ influx via receptor-mediated channels.
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PMID:Expression and cellular localization of a modified type 1 ryanodine receptor and L-type channel proteins in non-muscle cells. 1239 83


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