UNIPROT:P21817 - FACTA Search

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Query: UNIPROT:P21817 (RyR1)
1,154 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ryanodine receptors (RyRs) are the major sarcoplasmic reticulum calcium-release channels required for excitation-contraction coupling in skeletal and cardiac muscle. Mutations in RyRs have been linked to several human diseases. Mutations in the cardiac isoform of RyR2 are associated with catecholaminergic polymorphic ventricular arrhythmias (CPVT), and arrhythmogenic right ventricular dysplasia type 2 (ARVD2), whereas mutations in the skeletal muscle isoform (RyR1) are linked to malignant hyperthermia (MH) and central core disease (CCD). RyRs are modulated by several other proteins, including the FK506 binding proteins (FKBPs), FKBP12 and FKBP12.6. These immunophilins appear to stabilize a closed state of the channel and are important for cooperative interactions among the subunits of RyRs. This review discusses the regulation of RyRs by FKBPs and the possibility that defective modulation of RyR2 by FKBP12.6 could play a role in heart failure, CPVT, and ARVD2. Also discussed are the consequences of FKBP12 depletion to skeletal muscle and the possibility of FKBP12 involvement in certain forms of MH or CCD.
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PMID:Regulation of ryanodine receptors by FK506 binding proteins. 1545 14

To better understand the role of the transient expression of ryanodine receptor (RyR) type 3 (RyR3) on Ca(2+) homeostasis during the development of skeletal muscle, we have analyzed the effect of expression levels of RyR3 and RyR1 on the overall physiology of cultured myotubes and muscle fibers. Dyspedic myotubes were infected with RyR1 or RyR3 containing virions at 0.2, 0.4, 1.0, and 4.0 moieties of infection (MOI), and analysis of their pattern of expression, caffeine sensitivity, and resting free Ca(2+) concentration ([Ca(2+)](r)) was performed. Although increased MOI resulted in increased expression of each receptor isoform, it did not significantly affect the immunopattern of RyRs or the expression levels of calsequestrin, triadin, or FKBP-12. Interestingly, myotubes expressing RyR3 always had significantly higher [Ca(2+)](r) and lower caffeine EC(50) than did cells expressing RyR1. Although some of the increased sensitivity of RyR3 to caffeine could be attributed to the higher [Ca(2+)](r) in RyR3-expressing cells, studies of [(3)H]ryanodine binding demonstrated intrinsic differences in caffeine sensitivity between RyR1 and RyR3. Tibialis anterior (TA) muscle fibers at different stages of postnatal development exhibited a transient increase in [Ca(2+)](r) coordinately with their level of RyR3 expression. Similarly, adult soleus fibers, which also express RyR3, had higher [Ca(2+)](r) than did adult TA fibers, which exclusively express RyR1. These data show that in skeletal muscle, RyR3 increases [Ca(2+)](r) more than RyR1 does at any expression level. These data suggest that the coexpression of RyR1 and RyR3 at different levels may constitute a novel mechanism by which to regulate [Ca(2+)](r) in skeletal muscle.
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PMID:Expression levels of RyR1 and RyR3 control resting free Ca2+ in skeletal muscle. 1554 69

The ryanodine receptor-calcium release channel complex (RyR) plays a pivotal role in excitation-contraction coupling in skeletal and cardiac muscle. RyR channel activity is modulated by interaction with FK506-binding protein (FKBP), and disruption of the RyR-FKBP association has been implicated in cardiomyopathy, cardiac hypertrophy, and heart failure. Evidence for an interaction between RyR and FKBP is well documented, both in skeletal muscle (RyR1-FKBP12) and in cardiac muscle (RyR2-FKBP12.6), however definition of the FKBP-binding site remains elusive. Early reports proposed interaction of a short RyR central domain with FKBP12/12.6, however this site has been questioned, and recently an alternative FKBP12.6 interaction site has been identified within the N-terminal half of RyR2. In this study, we report evidence for the human RyR2 C-terminal domain as a novel FKBP12.6-binding site. Using competition binding assays, we find that short C-terminal RyR2 fragments can displace bound FKBP12.6 from the native RyR2, although they are unable to exclusively support interaction with FKBP12.6. However, expression of a large RyR2 C-terminal construct in mammalian cells encompassing the pore-forming transmembrane domains exhibits rapamycin-sensitive binding specifically to FKBP12.6 but not to FKBP12. We also obtained some evidence for involvement of the RyR2 N-terminal, but not the central domain, in FKBP12.6 interaction. Our studies suggest that a novel interaction site for FKBP12.6 may be present at the RyR2 C terminus, proximal to the channel pore, a sterically appropriate location that would enable this protein to play a central role in the modulation of this critical ion channel.
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PMID:Interaction of FKBP12.6 with the cardiac ryanodine receptor C-terminal domain. 1559 Oct 45

Ca+-induced Ca2+ release (CICR) in the heart involves local Ca2+ signaling between sarcolemmal L-type Ca2+ channels (dihydropyridine receptors, DHPRs) and type 2 ryanodine receptors (RyR2s) in the sarcoplasmic reticulum (SR). We reconstituted cardiac-like CICR by expressing a cardiac dihydropyridine-insensitive (T1066Y/Q1070M) alpha1-subunit (alpha1CYM) and RyR2 in myotubes derived from RyR1-knockout (dyspedic) mice. Myotubes expressing alpha1CYM and RyR2 were vesiculated and exhibited spontaneous Ca2+ oscillations that resulted in chaotic and uncontrolled contractions. Coexpression of FKBP12.6 (but not FKBP12.0) with alpha1CYM and RyR2 eliminated vesiculations and reduced the percentage of myotubes exhibiting uncontrolled global Ca2+ oscillations (63% and 13% of cells exhibited oscillations in the absence and presence of FKBP12.6, respectively). alpha1CYM/RyR2/FKBP12.6-expressing myotubes exhibited robust and rapid electrically evoked Ca2+ transients that required extracellular Ca2+. Depolarization-induced Ca2+ release in alpha1CYM/RyR2/FKBP12.6-expressing myotubes exhibited a bell-shaped voltage dependence that was fourfold larger than that of myotubes expressing alpha1CYM alone (maximal fluorescence change was 2.10 +/- 0.39 and 0.54 +/- 0.07, respectively), despite similar Ca2+ current densities. In addition, the gain of CICR in alpha1CYM/RyR2/FKBP12.6-expressing myotubes exhibited a nonlinear voltage dependence, being considerably larger at threshold potentials. We used this molecular model of local alpha1C-RyR2 signaling to assess the ability of FKBP12.6 to inhibit spontaneous Ca2+ release via a phosphomimetic mutation in RyR2 (S2808D). Electrically evoked Ca2+ release and the incidence of spontaneous Ca2+ oscillations did not differ in wild-type RyR2- and S2808D-expressing myotubes over a wide range of FKBP12.6 expression. Thus a negative charge at S2808 does not alter in situ regulation of RyR2 by FKBP12.6.
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PMID:Reconstitution of local Ca2+ signaling between cardiac L-type Ca2+ channels and ryanodine receptors: insights into regulation by FKBP12.6. 1604 53

The immunophilin, FK506-binding protein (FKBP12), is an essential component of the ryanodine receptor channel complex of skeletal muscle (RyR1) and modulates intracellular calcium signaling from the endoplasmic reticulum. The cardiac muscle RyR isoform (RyR2) specifically associates with a distinct FKBP isoform, FKBP12.6. Previous studies have led to the proposal that the central domain of RyR1 exclusively mediates the interaction with FKBP12. To characterize the topography of the FKBP12.6 binding site on the human cardiac RyR2, we have applied complementary protein-protein interaction methods using both in vivoyeast two-hybrid analysis and in vitroimmunoprecipitation experiments. Our results indicate an absence of interaction of FKBP12/12.6 with fragments containing the central domain of either RyR1, RyR2, or RyR3. Furthermore, no interaction was detected between FKBP12.6 with a series of overlapping fragments encompassing the entire RyR2, either individually or in multiple combination. We also found that a distinct, alternatively spliced variant of FKBP12.6 was unable to interact with RyR. In contrast, we successfully demonstrated a robust association between the cytoplasmic domain of transforming growth factor-beta receptor type I and both FKBP12 and FKBP12.6 in parallel positive control experiments, as well as between native RyR2 and FKBP12.6. These results suggest that the specific interaction of FKBP12.6 with RyR2, and generally of FKBPs with any RyR isoform, is not readily reconstituted by peptide fragments corresponding to central RyR domains. Further structural analysis will be necessary to unravel this intricate signaling system and the current model of FKBP12-RyR interaction via a single, central RyR epitope may therefore require revision.
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PMID:Central domain of the human cardiac muscle ryanodine receptor does not mediate interaction with FKBP12.6. 1604 46

The cardiac isoform of the ryanodine receptor (RyR2) from dog binds predominantly a 12.6-kDa isoform of the FK506-binding protein (FKBP12.6), whereas RyR2 from other species binds both FKBP12.6 and the closely related isoform FKBP12. The role played by FKBP12.6 in modulating calcium release by RyR2 is unclear at present. We have used cryoelectron microscopy and three-dimensional (3D) reconstruction techniques to determine the binding position of FKBP12.6 on the surface of canine RyR2. Buffer conditions that should favor the "open" state of RyR2 were used. Quantitative comparison of 3D reconstructions of RyR2 in the presence and absence of FKBP12.6 reveals that FKBP12.6 binds along the sides of the square-shaped cytoplasmic region of the receptor, adjacent to domain 9, which forms part of the four clamp (corner-forming) structures. The location of the FKBP12.6 binding site on "open" RyR2 appears similar, but slightly displaced (by 1-2 nm) from that found previously for FKBP12 binding to the skeletal muscle ryanodine receptor that was in the buffer that favors the "closed" state. The conformation of RyR2 containing bound FKBP12.6 differs considerably from that depleted of FKBP12.6, particularly in the transmembrane region and in the clamp structures. The x-ray structure of FKBP12.6 was docked into the region of the 3D reconstruction that is attributable to bound FKBP12.6, to show the relative orientations of amino acid residues (Gln-31, Asn-32, Phe-59) that have been implicated as being critical in interactions with RyR2. A thorough understanding of the structural basis of RyR2-FKBP12.6 interaction should aid in understanding the roles that have been proposed for FKBP12.6 in heart failure and in certain forms of sudden cardiac death.
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PMID:Three-dimensional visualization of FKBP12.6 binding to an open conformation of cardiac ryanodine receptor. 1621 74

The 12 kDa FK506-binding protein (FKBP12) constitutively binds to the calcium release channel RyR1. Removal of FKBP12 using FK506 or rapamycin causes an increased open probability and an increase in the frequency of sub-conductance states in RyR1. Using cryo-electron microscopy and single-particle image processing, we have determined the 3D difference map of FKBP12 associated with RyR1 at 16 A resolution that can be fitted with the atomic model of FKBP12 in a unique orientation. This has allowed us to better define the surfaces of close apposition between FKBP12 and RyR1. Our results shed light on the role of several FKBP12 residues that had been found critical for the specificity of the RyR1-FKBP12 interaction. As predicted from previous immunoprecipitation studies, our results suggest that Gln3 participates directly in this interaction. The orientation of RyR1-bound FKBP12, with part of its FK506 binding site facing towards RyR1, allows us to propose how FK506 is involved in the dissociation of FKBP12 from RyR1.
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PMID:Structural characterization of the RyR1-FKBP12 interaction. 1640 11

Ryanodine receptor 1 (RYR1) gene mutations are associated with central core disease (CCD), multiminicore disease (MmD) and malignant hyperthermia (MH), and have been reported to be responsible for 47-67% of patients with CCD and rare cases with MmD. However, to date, the true frequency and distribution of the mutations along the RYR1 gene have not been determined yet, since mutation screening has been limited to three 'hot spots', with particular attention to the C-terminal region. In this study, 27 unrelated Japanese CCD patients were included. Clinical histories and muscle biopsies were carefully reviewed. We sequenced all the 106 exons encoding RYR1 with their flanking exon-intron boundaries, and identified 20 novel and 3 previously reported heterozygous missense mutations in 25 of the 27 CCD patients (93%), which is a much higher mutation detection rate than that perceived previously. Among them, six were located outside the known 'hot spots'. Sixteen of 27 (59%) CCD patients had mutations in the C-terminal 'hot spot'. Three CCD patients had a probable autosomal recessive disease with two heterozygous mutations. Patients with C-terminal mutations had earlier onset and rather consistent muscle pathology characterized by the presence of distinct cores in almost all type 1 fibres, interstitial fibrosis and type 2 fibre deficiency. In contrast, patients with mutations outside the C-terminal region had milder clinical phenotype and harbour more atypical cores in their muscle fibres. We also sequenced two genes encoding RYR1-associated proteins as candidate causative genes for CCD: the 12 kD FK506-binding protein (FKBP12) and the alpha1 subunit of L-type voltage-dependent calcium channel or dihydropyridine receptor (CACNA1S). However, no mutation was found, suggesting that these genes may not, or only rarely, be responsible for CCD. Our results indicate that CCD may be caused by RYR1 mutations in the majority of patients.
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PMID:Central core disease is due to RYR1 mutations in more than 90% of patients. 1662 18

Bastadin-5, a brominated macro-dilactam from the marine sponge Ianthella basta, enhances release of Ca2+ from stores within the sarcoplasmic reticulum (SR) of muscle and nonmuscle cells by modulating RyR1/FKBP12 complex. Analogues of bastadin-5 present desirable targets for SAR studies to shed light on the gating mechanism and locus of bastadin-5 binding on these heteromeric channels that mediate essential steps in early coupling of membrane excitation to Ca2+ signaling cascades. Simple, ring-constrained analogues of bastadin-5 were synthesized from substituted benzaldehydes in a convergent manner, featuring an efficient S(N)Ar macroetherification, and evaluated in an assay that measures [3H]-ryanodine that is known to correlate with the functional open state of the Ca2+ channel. The simplified 14-membered ring, atropisomeric analogue (+/-)-7, like bastadin-5, enhanced ryanodine binding to the RyR1/FKBP12 complex (EC50 11 microM), however, unexpectedly, the corresponding achiral 18-membered ring analogue 14 potently inhibited binding (IC50 6 microM) under the same conditions. Structure-activity relationships of both families of cyclic analogues showed activity in a ryanodine binding assay that varied with substitutions of the Br atom on the trisubstituted aryl ring by various functional groups. The most active analogues were those that conserved the dibromocatechol ether moiety that corresponds to the 'western edge' of the bastadin-5 structure. These data suggest that cyclic analogues of bastadin-5 interact with the channel complex in a complex manner that can either enhance or inhibit channel activity.
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PMID:Simplified cyclic analogues of bastadin-5. Structure-activity relationships for modulation of the RyR1/FKBP12 Ca2+ channel complex. 1685 55

We have demonstrated recently that CICR (Ca2+-induced Ca2+ release) activity of RyR1 (ryanodine receptor 1) is held to a low level in mammalian skeletal muscle ('suppression' of the channel) and that this is largely caused by the interdomain interaction within RyR1 [Murayama, Oba, Kobayashi, Ikemoto and Ogawa (2005) Am. J. Physiol. Cell Physiol. 288, C1222-C1230]. To test the hypothesis that aberration of this suppression mechanism is involved in the development of channel dysfunctions in MH (malignant hyperthermia), we investigated properties of the RyR1 channels from normal and MHS (MH-susceptible) pig skeletal muscles with an Arg615-->Cys mutation using [3H]ryanodine binding, single-channel recordings and SR (sarcoplasmic reticulum) Ca2+ release. The RyR1 channels from MHS muscle (RyR1MHS) showed enhanced CICR activity compared with those from the normal muscle (RyR1N), although there was little or no difference in the sensitivity to several ligands tested (Ca2+, Mg2+ and adenine nucleotide), nor in the FKBP12 (FK506-binding protein 12) regulation. DP4, a domain peptide matching the Leu2442-Pro2477 region of RyR1 which was reported to activate the Ca2+ channel by weakening the interdomain interaction, activated the RyR1N channel in a concentration-dependent manner, and the highest activity of the affected channel reached a level comparable with that of the RyR1MHS channel with no added peptide. The addition of DP4 to the RyR1MHS channel produced virtually no further effect on the channel activity. These results suggest that stimulation of the RyR1MHS channel caused by affected inter-domain interaction between regions 1 and 2 is an underlying mechanism for dysfunction of Ca2+ homoeostasis seen in the MH phenotype.
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PMID:Postulated role of interdomain interaction between regions 1 and 2 within type 1 ryanodine receptor in the pathogenesis of porcine malignant hyperthermia. 1710 40

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