The Ryanodine Receptor-Ca2+ Release Channel Complex of Skeletal Muscle Sarcoplasmic Reticulum

Lai, F. Anthony; Misra, Manoj; Xu, Le; Smith, Hilary A.; Meissner, Gerhard

doi:10.1016/s0021-9258(19)84773-7

Cited by 219 publications

(34 citation statements)

References 49 publications

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“…To see this figure in color, go online. coinciding with the four different binding affinities per tetrameter found in experiments (9).…”

Section: Thermodynamics Of Ryd Bindingsupporting

confidence: 85%

“…This study showed that Ryd can strongly bind to the cavity with the preferable interactions between the pyrrolic ring and the R 4892 AGGG-F 4921 residues. Although this study used the closed structure of RyR1, whose cavity would have enough space for only one Ryd, it sheds insight into four possible distinguishable binding affinities experimentally found in RyRs (9,45), and helps in explaining any mutagenesis that significantly modified the binding affinities in RyRs and thus the action of Ryd. We also reported a parameter set for Ryd that can be used for investigating the effects of Ryd on the opening and closure of RyRs.…”

Section: Discussionmentioning

confidence: 99%

“…The exact structural mechanisms arising from the different binding affinities and locations of the binding sites remain uncertain. While the binding to the high-affinity site may result in the opening of RyRs, the subsequent binding to the low-affinity sites may induce an opposite effect-a complete closure of RyRs (9). The binding is virtually irreversible because of difficulty in washing out the ligand.…”

Section: Introductionmentioning

confidence: 99%

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Mapping Ryanodine Binding Sites in the Pore Cavity of Ryanodine Receptors

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Perissinotti

Miranda

et al. 2017

Biophysical Journal

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Ryanodine (Ryd) irreversibly targets ryanodine receptors (RyRs), a family of intracellular calcium release channels essential for many cellular processes ranging from muscle contraction to learning and memory. Little is known of the atomistic details about how Ryd binds to RyRs. In this study, we used all-atom molecular dynamics simulations with both enhanced and bidirectional sampling to gain direct insights into how Ryd interacts with major residues in RyRs that were experimentally determined to be critical for its binding. We found that the pyrrolic ring of Ryd displays preference for the RAGGG-F residues in the cavity of RyR1, which explain the effects of the corresponding mutations in RyR2 in experiments. Particularly, the mutant Q4933A (or Q4863A in RyR2) critical for both the gating and Ryd binding not only has significantly less interaction with Ryd than the wild-type, but also yields more space for Ryd and water molecules in the cavity. These results describe clear binding modes of Ryd in the RyR cavity and offer structural mechanisms explaining functional data collected on RyR blockade.

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“…To see this figure in color, go online. coinciding with the four different binding affinities per tetrameter found in experiments (9).…”

Section: Thermodynamics Of Ryd Bindingsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mapping Ryanodine Binding Sites in the Pore Cavity of Ryanodine Receptors

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Perissinotti

Miranda

et al. 2017

Biophysical Journal

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“…The binding of [ 3 H]ryanodine to isolated membrane vesicles has provided detailed information on the distri-bution and density of receptors in membrane populations, the affinity of the sites on the receptor, the rates of association and dissociation of ryanodine, and the number of sites on the receptor (Lai et al, 1989;Pessah and Zimanyi, 1991;McGrew et al, 1989;Wang et al, 1993;Coronado et al, 1994). Variations in the quantity of [ 3 H]ryanodine bound to populations of receptor in the presence of ligands known to modify Ca 2 ϩ -release channel function suggest that the interaction of the alkaloid with its receptor may be influenced by channel gating (Holmberg and Williams, 1990 a ;Chu et al, 1990;Hawkes et al, 1992;Meissner and El-Hashem, 1992).…”

Section: Introductionmentioning

confidence: 99%

Interactions of a Reversible Ryanoid (21-Amino-9α-Hydroxy-Ryanodine) with Single Sheep Cardiac Ryanodine Receptor Channels

Tanna

Welch

Ruest

et al. 1998

The Journal of General Physiology

101

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The binding of ryanodine to a high affinity site on the sarcoplasmic reticulum Ca2+-release channel results in a dramatic alteration in both gating and ion handling; the channel enters a high open probability, reduced-conductance state. Once bound, ryanodine does not dissociate from its site within the time frame of a single channel experiment. In this report, we describe the interactions of a synthetic ryanoid, 21-amino-9α-hydroxy-ryanodine, with the high affinity ryanodine binding site on the sheep cardiac sarcoplasmic reticulum Ca2+-release channel. The interaction of 21-amino-9α-hydroxy-ryanodine with the channel induces the occurrence of a characteristic high open probability, reduced-conductance state; however, in contrast to ryanodine, the interaction of this ryanoid with the channel is reversible under steady state conditions, with dwell times in the modified state lasting seconds. By monitoring the reversible interaction of this ryanoid with single channels under voltage clamp conditions, we have established a number of novel features of the ryanoid binding reaction. (a) Modification of channel function occurs when a single molecule of ryanoid binds to the channel protein. (b) The ryanoid has access to its binding site only from the cytosolic side of the channel and the site is available only when the channel is open. (c) The interaction of 21-amino-9α-hydroxy-ryanodine with its binding site is influenced strongly by transmembrane voltage. We suggest that this voltage dependence is derived from a voltage-driven conformational alteration of the channel protein that changes the affinity of the binding site, rather than the translocation of the ryanoid into the voltage drop across the channel.

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“…Ryanodine, a plant alkaloid that was originally found to affect the Ca 2+ release channel, has dual effects on the channel. It stabilizes subconductance states at lower concentrations, but becomes inhibitory at higher levels (Lai et al 1989). Various adenosine nucleotides are able to activate RyRs with ATP being the most potent.…”

Section: Structurementioning

confidence: 99%

Ras Association (RalGDS/AF-6) Domain Family 6

2018

Encyclopedia of Signaling Molecules

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The Ryanodine Receptor-Ca2+ Release Channel Complex of Skeletal Muscle Sarcoplasmic Reticulum

Cited by 219 publications

References 49 publications

Mapping Ryanodine Binding Sites in the Pore Cavity of Ryanodine Receptors

Mapping Ryanodine Binding Sites in the Pore Cavity of Ryanodine Receptors

Interactions of a Reversible Ryanoid (21-Amino-9α-Hydroxy-Ryanodine) with Single Sheep Cardiac Ryanodine Receptor Channels

Ras Association (RalGDS/AF-6) Domain Family 6

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