Ryanodine

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Angela F. Dulhunty - One of the best experts on this subject based on the ideXlab platform.

  • regulation of Ryanodine receptors by calsequestrin effect of high luminal ca2 and phosphorylation
    Biophysical Journal, 2005
    Co-Authors: Nicole A. Beard, Magdolna Varsányi, Marco G Casarotto, Angela F. Dulhunty
    Abstract:

    Calsequestrin, the major calcium sequestering protein in the sarcoplasmic reticulum of muscle, forms a quaternary complex with the Ryanodine receptor calcium release channel and the intrinsic membrane proteins triadin and junctin. We have investigated the possibility that calsequestrin is a luminal calcium concentration sensor for the Ryanodine receptor. We measured the luminal calcium concentration at which calsequestrin dissociates from the Ryanodine receptor and the effect of calsequestrin on the response of the Ryanodine receptor to changes in luminal calcium. We provide electrophysiological and biochemical evidence that: 1), luminal calcium concentration of ≥4 mM dissociates calsequestrin from junctional face membrane, whereas in the range of 1–3 mM calsequestrin remains attached; 2), the association with calsequestrin inhibits Ryanodine receptor activity, but amplifies its response to changes in luminal calcium concentration; and 3), under physiological calcium conditions (1 mM), phosphorylation of calsequestrin does not alter its ability to inhibit native Ryanodine receptor activity when the anchoring proteins triadin and junctin are present. These data suggest that the quaternary complex is intact in vivo, and provides further evidence that calsequestrin is involved in the sarcoplasmic reticulum calcium signaling pathway and has a role as a luminal calcium sensor for the Ryanodine receptor.

  • a structural requirement for activation of skeletal Ryanodine receptors by peptides of the dihydropyridine receptor ii iii loop
    Journal of Biological Chemistry, 2000
    Co-Authors: Marco G Casarotto, F Gibson, Suzi M Pace, Suzanne M Curtis, Mark Mulcair, Angela F. Dulhunty
    Abstract:

    Abstract The solution structures of three related peptides (A1, A2, and A9) corresponding to the Thr671–Leu690 region of the skeletal muscle dihydropyridine receptor II-III loop have been investigated using nuclear magnetic resonance spectroscopy. Peptide A1, the native sequence, is less effective in activating Ryanodine receptor calcium release channels than A2 (Ser687 to Ala substitution). Peptide A9, Arg681–Ser687, does not activate Ryanodine receptors. A1 and A2 are helical from their N terminus to Lys685 but are generally unstructured from Lys685 to the C terminus. The basic residues Arg681–Lys685, essential for A1 activation of Ryanodine receptors, are located at the C-terminal end of the α-helix. Peptide A9 was found to be unstructured. Differences between A1 and A2 were observed in the C-terminal end of the helix (residues 681–685), which was less ordered in A1, and in the C-terminal region of the peptide, which exhibited greater flexibility in A1. Predicted low energy models suggest that an electrostatic interaction between the hydroxyl oxygen of Ser687 and the guanidino moiety of Arg683 is lost with the Ser687Ala substitution. The results show that the more structured peptides are more effective in activating Ryanodine receptors.

  • single channel activity of the Ryanodine receptor calcium release channel is modulated by fk 506
    FEBS Letters, 1994
    Co-Authors: Gerard P Ahern, Pauline R. Junankar, Angela F. Dulhunty
    Abstract:

    The immunosuppressant drug FK-506 (3-20 microM) increased the open probability of Ryanodine receptor calcium release channels, formed by incorporation of terminal cisternae vesicles from rabbit skeletal muscle into lipid bilayers, with cis (cytoplasmic) calcium concentrations between 10(-7) M and 10(-3) M. FK-506 increased mean current and channel open time and induced long sojourns at subconductance levels that were between 28% and 38% of the maximum conductance and were distinct from the Ryanodine-induced subconductance level at about 45% of the maximum conductance. FK-506 relieved the Ca2+ inactivation of the Ryanodine receptor seen at 10(-3) M Ca2+. The results are consistent with FK-506 removal of FK-506 binding protein from the Ryanodine receptor.

  • Extra-Junctional Ryanodine Receptors in the Terminal Cisternae of Mammalian Skeletal Muscle Fibres
    Proceedings of The Royal Society B: Biological Sciences, 1992
    Co-Authors: Angela F. Dulhunty, Pauline R. Junankar, Carolyn Stanhope
    Abstract:

    The distribution of Ryanodine receptor calcium-release channels over the terminal cisternae (TC) membrane of skeletal muscle fibres was examined by using immunogold electron microscopy. Two monoclonal antibodies (5C3 and 8E2) that bound to monomers of the Ryanodine receptor protein on Western blots of SDS-polyacrylamide gels were used to locate calcium-release channels in longitudinal sections of rat sternomastoid and diaphragm fibres. Up to 21% of 5C3 binding on TC membranes was extra-junctional, compared with 46% for 8E2. Binding of 8E2 to the fibres was less than half that of 5C3, possibly because of steric shielding of the 8E2 antigenic site at the junction. The distances between neighbouring particles in clusters was 20-40 nm, i.e. the distance between subunits of the Ryanodine receptor or between neighbouring foot structures. We suggest that, during activation, extra-junctional Ryanodine receptors may release Ca$^{2+}$ directly into the myoplasm, rather than into the restricted space of the triad junction.

Barbara E. Ehrlich - One of the best experts on this subject based on the ideXlab platform.

  • reversible block of the calcium release channel Ryanodine receptor by protamine a heparin antidote
    Molecular Biology of the Cell, 2000
    Co-Authors: Peter Koulen, Barbara E. Ehrlich
    Abstract:

    : Channel activity of the calcium release channel from skeletal muscle, Ryanodine receptor type 1, was measured in the presence and absence of protamine sulfate on the cytoplasmic side of the channel. Single-channel activity was measured after incorporating channels into planar lipid bilayers. Optimally and suboptimally calcium-activated calcium release channels were inactivated by the application of protamine to the cytoplasmic side of the channel. Recovery of channel activity was not observed while protamine was present. The addition of protamine bound to agarose beads did not change channel activity, implying that the mechanism of action involves an interaction with the Ryanodine receptor rather than changes in the bulk calcium concentration of the medium. The block of channel activity by protamine could be reversed either by removal by perfusion with buffer or by the addition of heparin to the cytoplasmic side of the channel. Microinjection of protamine into differentiated C(2)C(12) mouse muscle cells prevented caffeine-induced intracellular calcium release. The results suggest that protamine acts on the Ryanodine receptor in a similar but opposite manner from heparin and that protamine can be used as a potent, reversible inhibitor of Ryanodine receptor activity.

  • bell shaped calcium response curves of ins 1 4 5 p3 and calcium gated channels from endoplasmic reticulum of cerebellum
    Nature, 1991
    Co-Authors: Ilya Bezprozvanny, James Watras, Barbara E. Ehrlich
    Abstract:

    RELEASE of calcium from intracellular stores occurs by two pathways, an inositol 1,4,5-trisphosphate (InsP3)-gated channel1–3 and a calcium-gated channel (Ryanodine receptor)4–6. Using specific antibodies, both receptors were found in Purkinje cells of cerebellum7,8. We have now compared the functional properties of the channels corresponding to the two receptors by incorporating endoplasmic reticulum vesicles from canine cerebellum into planar bilayers. InsP3-gated channels were observed most frequently. Another channel type was activated by adenine nucleotides or caffeine, inhibited by ruthenium red, and modified by Ryanodine, characteristics of the Ryanodine receptor/channel6. The open probability of both channel types displayed a bell-shaped curve for dependence on calcium. For the InsP3-gated channel, the maximum probability of opening occurred at 0.2 µM free calcium, with sharp decreases on either side of the maximum. Maximum activity for the Ryanodine receptor/channel was maintained between 1 and 100 µM calcium. Thus, within the physiological range of cytoplasmic calcium, the InsP3-gated channel itself allows positive feed-back and then negative feedback for calcium release, whereas the Ryanodine receptor/channel behaves solely as a calcium-activated channel. The existence in the same cell of two channels with different responses to calcium and different ligand sensitivities provides a basis for complex patterns of intracellular calcium regulation.

David H Maclennan - One of the best experts on this subject based on the ideXlab platform.

  • Ryanodine sensitizes the cardiac ca2 release channel Ryanodine receptor isoform 2 to ca2 activation and dissociates as the channel is closed by ca2 depletion
    Proceedings of the National Academy of Sciences of the United States of America, 2001
    Co-Authors: Guo Guang Du, Vijay K Khanna, David H Maclennan
    Abstract:

    In single-channel recordings, the rabbit cardiac Ca2+ release channel (RyR2) is converted to a fully open subconductance state with about 50% of full conductance by micromolar concentrations of Ryanodine. At +30 mV, corresponding to a luminal to cytoplasmic cation current, the probability of opening (Po) of Ryanodine-modified channels was only marginally altered at pCa 10 (pCa = −log10 Ca concentration). However, at −30 mV, the Po was highly sensitive to Ca2+ added to the cis (cytoplasmic) side and, at pCa 10, was reduced to less than 0.27. The EC50 value for channel opening was about pCa 8. No significant Ca2+ inactivation was observed for Ryanodine-modified channels at either −30 mV or +30 mV. The opening of unmodified Ca2+ channels is Ca2+ sensitive, with an EC50 value of about pCa 6 (two orders of magnitude less sensitive than Ryanodine-modified channels) and IC50 values of pCa 2.2 at −30 mV and 2.5 at +30 mV. Mg2+ decreased the Po of Ryanodine-modified channels at low Ca2+ concentrations at both −30 and +30 mV. Caffeine, ATP, and ruthenium red were modulators of the Po of Ryanodine-modified channels. In a [3H]Ryanodine binding assay, [3H]Ryanodine dissociation from the high-affinity binding site was found to be Ca2+ sensitive, with an IC50 of pCa 7.1. High concentrations of unlabeled Ryanodine prevented [3H]Ryanodine dissociation, but ruthenium red accelerated dissociation. These results suggest that Ryanodine sensitizes Ca2+ activation of the Ca2+ release channel and desensitizes Ca2+ inactivation through an allosteric interaction. [3H]Ryanodine dissociates from the high-affinity site when the channel is closed by removal of Ca2+, implying that high-affinity Ryanodine and Ca2+ binding sites are linked through either short- or long-range interactions, probably involving conformational changes.

  • identification of calmodulin ca 2 and ruthenium red binding domains in the ca2 release channel Ryanodine receptor of rabbit skeletal muscle sarcoplasmic reticulum
    Journal of Biological Chemistry, 1994
    Co-Authors: Shihao Chen, David H Maclennan
    Abstract:

    Abstract cDNAs encoding trpE fusion proteins containing fragments of the skeletal muscle Ca2+ release channel (Ryanodine receptor) were expressed in bacteria. The fusion proteins, which covered about 90% of the linear sequence of the Ryanodine receptor, were used to identify calmodulin- (CaM), Ca(2+)-, and ruthenium red-binding regions in the Ryanodine receptor through the use of 125I-CaM, 45Ca2+, and ruthenium red overlay procedures. Six Ca(2+)-dependent CaM-binding domains were detected in the skeletal muscle Ryanodine receptor. Strong CaM-binding domains were localized in regions 6, 11, 12, and 13, in subregions 6b, 11b, and 13b, and in short sequences 6b3, 11b1, and 13b2, lying between amino acid residues 2063 and 2091, 3611 and 3642, and 4303 and 4328. Weaker CaM-binding domains were localized in regions 4, 9, and 10 and in subregions 4b, 9b, and 10a, lying between residues 921 and 1173, 2804 and 2930, and 2961 and 3084. Most of these CaM-binding domains encompassed all or part of previously predicted CaM-binding sites. Strong 45Ca(2+)- and ruthenium red-binding sites domains were localized in the NH2- and COOH-terminal regions of the Ryanodine receptor and in regions 6, 12, and 13. The 45Ca(2+- and ruthenium red-binding sites in regions 6 and 12 were localized in subregions 6b and 12b, lying between residues 1861-2094 and 3657-3776. These data together with earlier studies (Chen, S. R. W., Zhang, L., and MacLennan, D. H. (1992) J. Biol. Chem. 267, 23318-23326), show that strong CaM-, Ca(2+)-, and ruthenium red-binding domains are colocalized in the skeletal muscle Ryanodine receptor.

Cecilia Hidalgo - One of the best experts on this subject based on the ideXlab platform.

  • Image_1_Ryanodine Receptor-Mediated Calcium Release Has a Key Role in Hippocampal LTD Induction.TIF
    2018
    Co-Authors: Alejandra Arias-cavieres, Pablo Munoz, Gina Sanchez, Genaro C. Barrientos, Claudio Elgueta, Cecilia Hidalgo
    Abstract:

    The induction of both long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission entails pre- and postsynaptic Ca2+ signals, which represent transient increments in cytoplasmic free Ca2+ concentration. In diverse synapse types, Ca2+ release from intracellular stores contributes to amplify the Ca2+ signals initially generated by activation of neuronal Ca2+ entry pathways. Here, we used hippocampal slices from young male rats to evaluate whether pharmacological activation or inhibition of Ca2+ release from the endoplasmic reticulum (ER) mediated by Ryanodine receptor (RyR) channels modifies LTD induction at Schaffer collateral-CA1 synapses. Pre-incubation of slices with Ryanodine (1 μM, 1 h) or caffeine (1 mM, 30 min) to promote RyR-mediated Ca2+ release facilitated LTD induction by low frequency stimulation (LFS), but did not affect the amplitude of synaptic transmission, the profiles of field excitatory postsynaptic potentials (fEPSP) or the paired-pulse (PP) responses. Conversely, treatment with inhibitory Ryanodine (20 μM, 1 h) to suppress RyR-mediated Ca2+ release prevented LTD induction, but did not affect baseline synaptic transmission or PP responses. Previous literature reports indicate that LTD induction requires presynaptic CaMKII activity. We found that 1 h after applying the LTD induction protocol, slices displayed a significant increase in CaMKII phosphorylation relative to the levels exhibited by un-stimulated (naïve) slices. In addition, LTD induction (1 h) enhanced the phosphorylation of the presynaptic protein Synapsin I at a CaMKII-dependent phosphorylation site, indicating that LTD induction stimulates presynaptic CaMKII activity. Pre-incubation of slices with 20 μM Ryanodine abolished the increased CaMKII and Synapsin I phosphorylation induced by LTD, whereas naïve slices pre-incubated with inhibitory Ryanodine displayed similar CaMKII and Synapsin I phosphorylation levels as naïve control slices. We posit that inhibitory Ryanodine suppressed LTD-induced presynaptic CaMKII activity, as evidenced by the suppression of Synapsin I phosphorylation induced by LTD. Accordingly, we propose that presynaptic RyR-mediated Ca2+ signals contribute to LTD induction at Schaffer collateral-CA1 synapses.

  • Ryanodine Receptor-Mediated Calcium Release Has a Key Role in Hippocampal LTD Induction
    Frontiers Media S.A., 2018
    Co-Authors: Alejandra Arias-cavieres, Pablo Munoz, Gina Sanchez, Cecilia Hidalgo, Genaro C. Barrientos, Claudio Elgueta
    Abstract:

    The induction of both long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission entails pre- and postsynaptic Ca2+ signals, which represent transient increments in cytoplasmic free Ca2+ concentration. In diverse synapse types, Ca2+ release from intracellular stores contributes to amplify the Ca2+ signals initially generated by activation of neuronal Ca2+ entry pathways. Here, we used hippocampal slices from young male rats to evaluate whether pharmacological activation or inhibition of Ca2+ release from the endoplasmic reticulum (ER) mediated by Ryanodine receptor (RyR) channels modifies LTD induction at Schaffer collateral-CA1 synapses. Pre-incubation of slices with Ryanodine (1 μM, 1 h) or caffeine (1 mM, 30 min) to promote RyR-mediated Ca2+ release facilitated LTD induction by low frequency stimulation (LFS), but did not affect the amplitude of synaptic transmission, the profiles of field excitatory postsynaptic potentials (fEPSP) or the paired-pulse (PP) responses. Conversely, treatment with inhibitory Ryanodine (20 μM, 1 h) to suppress RyR-mediated Ca2+ release prevented LTD induction, but did not affect baseline synaptic transmission or PP responses. Previous literature reports indicate that LTD induction requires presynaptic CaMKII activity. We found that 1 h after applying the LTD induction protocol, slices displayed a significant increase in CaMKII phosphorylation relative to the levels exhibited by un-stimulated (naïve) slices. In addition, LTD induction (1 h) enhanced the phosphorylation of the presynaptic protein Synapsin I at a CaMKII-dependent phosphorylation site, indicating that LTD induction stimulates presynaptic CaMKII activity. Pre-incubation of slices with 20 μM Ryanodine abolished the increased CaMKII and Synapsin I phosphorylation induced by LTD, whereas naïve slices pre-incubated with inhibitory Ryanodine displayed similar CaMKII and Synapsin I phosphorylation levels as naïve control slices. We posit that inhibitory Ryanodine suppressed LTD-induced presynaptic CaMKII activity, as evidenced by the suppression of Synapsin I phosphorylation induced by LTD. Accordingly, we propose that presynaptic RyR-mediated Ca2+ signals contribute to LTD induction at Schaffer collateral-CA1 synapses

  • calcium release by Ryanodine receptors mediates hydrogen peroxide induced activation of erk and creb phosphorylation in n2a cells and hippocampal neurons
    Cell Calcium, 2007
    Co-Authors: Ulrike Kemmerling, Pablo Munoz, Marioly Muller, Gina Sanchez, Maria Luz Aylwin, Eric Klann, Angelica M Carrasco, Cecilia Hidalgo
    Abstract:

    Abstract Hydrogen peroxide, which stimulates ERK phosphorylation and synaptic plasticity in hippocampal neurons, has also been shown to stimulate calcium release in muscle cells by promoting Ryanodine receptor redox modification (S-glutathionylation). We report here that exposure of N2a cells or rat hippocampal neurons in culture to 200 μM H2O2 elicited calcium signals, increased Ryanodine receptor S-glutathionylation, and enhanced both ERK and CREB phosphorylation. In mouse hippocampal slices, H2O2 (1 μM) also stimulated ERK and CREB phosphorylation. Preincubation with Ryanodine (50 μM) largely prevented the effects of H2O2 on calcium signals and ERK/CREB phosphorylation. In N2a cells, the ERK kinase inhibitor U0126 suppressed ERK phosphorylation and abolished the stimulation of CREB phosphorylation produced by H2O2, suggesting that H2O2 enhanced CREB phosphorylation via ERK activation. In N2a cells in calcium-free media, 200 μM H2O2 stimulated ERK and CREB phosphorylation, while preincubation with thapsigargin prevented these enhancements. These combined results strongly suggest that H2O2 promotes Ryanodine receptors redox modification; the resulting calcium release signals, by enhancing ERK activity, would increase CREB phosphorylation. We propose that Ryanodine receptor stimulation by activity-generated redox species produces calcium release signals that may contribute significantly to hippocampal synaptic plasticity, including plasticity that requires long-lasting ERK-dependent CREB phosphorylation.

Anthony W. Quail - One of the best experts on this subject based on the ideXlab platform.