An Anionic Ryanoid, 10-O-succinoylryanodol, Provides Insights into the Mechanisms Governing the Interaction of Ryanoids and the Subsequent Altered Function of Ryanodine-receptor Channels

Tanna, Bhavna; Welch, W. F.; Ruest, Luc; Sutko, John L.; Williams, Alan J.

doi:10.1085/jgp.200208753

Cited by 9 publications

(24 citation statements)

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“…[ Analysis of Ryanodine Interaction with Single Q4863A Mutant Channels-The interaction of ryanodine with individual Q4863A mutant channels was analyzed as described previously (18). In brief, durations in the normal and ryanodine-modified states were measured directly from digitized single channel recordings and were used to obtain the corresponding mean dwell times.…”

Section: Methodsmentioning

confidence: 99%

“…6. I4861A [18], I4862A [19], G4864A [21], L4865A [22], and I4867A [24] all had binding capacities in excess of 25% of the wt RyR2. In contrast, mutants F4846A [3], D4847A [4], T4849A [6], F4850A [7], F4851A [8], I4855A [12], V4856A [13], L4858A [15], L4859A [16], Q4863A [20], and I4866A [23] displayed binding capacities of 5% or less of wt RyR2 ( Fig.…”

Section: Construction and Expression Of Mutants In The Proposedmentioning

confidence: 99%

“…5e. Values of slope conductance of the unmodified and ryanodine-modified states are 796 Ϯ 5.7 and 448 Ϯ 6.8 pico- 4] 0.6 Ϯ 0.8 Ϫ Ϫ I4848A [5] 59 Ϯ 10 ϩ ϩ T4849A [6] 0.5 Ϯ 0.8 ϩ ϩ F4850A [7] 0.1 Ϯ 0.5 Ϫ Ϫ F4851A [8] 0.1 Ϯ 0.3 Ϫ Ϫ F4852A [9] 84 Ϯ 16 ϩ ϩ F4853A [10] 99 Ϯ 28 ϩ ϩ V4854A [11] 36 Ϯ 1.2 ϩ ϩ I4855A [12] 3.8 Ϯ 1.6 ϩ ϩ V4856A [13] 1.0 Ϯ 0.9 ϩ ϩ I4857A [14] 64 Ϯ 2.4 ϩ ϩ L4858A [15] 2.5 Ϯ 1.6 Ϫ Ϫ L4859A [16] 3.8 Ϯ 1.4 Ϫ Ϫ A4860G [17] 58 Ϯ 3.5 ϩ ϩ I4861A [18] 98 Ϯ 5.7 ϩ ϩ I4862A [19] 61 Ϯ 2.7 ϩ Ϫ Q4863A [20] 0.0 Ϯ 0.0 ϩ Ϫ G4864A [21] 93 Ϯ 4.3 ϩ ϩ L4865A [22] 87 Ϯ 7.1 ϩ ϩ I4866A [23] 5.1 Ϯ 1.8 Ϫ Ϫ I4867A [24] 25 Ϯ 6. siemens (n ϭ 3) and are comparable to those of the corresponding states of wt RyR2 channels (23). While the Q4863A [20] mutation produces a profound alteration in the kinetics of ryanodine interaction it does not seem to cause gross alterations in channel conduction or the modulation of gating by other ligands.…”

Section: Effect Of the Q4863a[20] Mutation On The Kinetic And Ligand mentioning

confidence: 99%

“…Voltage Influence of Ryanodine Interaction with Single Q4863A [20] Mutant Channels-It has been shown previously that the effects of several reversible ryanoids on single RyR2 channels are dependent on the transmembrane holding potential (15)(16)(17)(18). However, the question of whether ryanodine action is also dependent on the transmembrane potential cannot be addressed due to the irreversibility of ryanodine action on single wt RyR2 channels.…”

Section: Effect Of the Q4863a[20] Mutation On The Kinetic And Ligand mentioning

confidence: 99%

“…Unlike ryanodine, which modifies RyR in an irreversible manner on the time scale of single channel experiments, some ryanoids exhibit a reversible effect on single RyR channel function. These reversible ryanoids have provided useful probes for studying the mechanisms of ryanoidRyR interaction and have been used to demonstrate that ryanoid-RyR interaction is influenced by transmembrane voltage (15)(16)(17)(18). Comprehensive analyses of the binding properties of various ryanoids have revealed that the pyrrole locus at the 3-position of the ryanodine molecule is absolutely required for high affinity ryanodine binding to RyR.…”

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Residue Gln4863 within a Predicted Transmembrane Sequence of the Ca2+ Release Channel (Ryanodine Receptor) Is Critical for Ryanodine Interaction

Wang

Zhang

Bolstad

et al. 2003

Journal of Biological Chemistry

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Despite the pivotal role of ryanodine in ryanodine receptor (RyR) research, the molecular basis of ryanodine-RyR interaction remains largely undefined. We investigated the role of the proposed transmembrane helix TM10 in ryanodine interaction and channel function. Each amino acid residue within the TM10 sequence, 4844 2؉ . Interestingly these two groups of mutants, each with similar properties, are largely located on opposite sides of the predicted TM10 helix. Single channel analyses revealed that mutation Q4863A dramatically altered the kinetics and apparent affinity of ryanodine interaction with single RyR2 channels and abolished the effect of ryanodol, an analogue of ryanodine, whereas the single channel conductance of the Q4863A mutant and its responses to caffeine, ATP, and Mg 2؉ were comparable to those of the wild type channels. Furthermore the effect of ryanodine on single Q4863A mutant channels was influenced by the transmembrane holding potential. Together these results suggest that the TM10 sequence and in particular the Q4863 residue constitute an important determinant of ryanodine interaction.Ryanodine receptors (RyRs) 1 are a family of intracellular Ca 2ϩ release channels located in the sarco(endo)plasmic reticulum of a variety of cells. They play an essential role in various cellular functions including excitation-contraction coupling, fertilization, and apoptosis (1-7). Three RyR isoforms, RyR1, RyR2, and RyR3, are expressed in mammalian tissues. Mutations in the RyR1 gene have been linked to two human diseases, malignant hyperthermia and central core disease (8 -10), while mutations in the RyR2 genes are associated with polymorphic ventricular tachycardia and arrhythmogenic right ventricular cardiomyopathy type 2 (11, 12). To understand the impact of the disease-causing mutations and hence the molecular and cellular basis of the diseases, detailed knowledge of the structure-function relationships of RyRs is required.One of the most widely used probes for studying the structure and function of RyRs is ryanodine, a plant alkaloid. The high affinity and specificity of the interaction of ryanodine with RyRs has facilitated the identification, purification, and cloning of the channel (2-5). Ryanodine has also been used to investigate the structural changes associated with channel gating and the mechanisms of ion conduction. Large ryanodineinduced conformational changes in the three-dimensional structure of RyR, in particular in the cytoplasmic assembly, have been observed (13). By monitoring the actions of ryanodine on single RyR channels it has been established that this ligand causes profound alterations in channel function. Interactions of ryanodine with a high affinity site on the channel induce the occurrence of a reduced conductance state with increased open probability, producing an overall effect of channel activation. In the presence of high micromolar to millimolar concentrations of ryanodine the RyR channel closes (5,14).While the functional effects of ryanodine have been well characte...

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Section: Methodsmentioning

confidence: 99%

Section: Construction and Expression Of Mutants In The Proposedmentioning

confidence: 99%

Section: Effect Of the Q4863a[20] Mutation On The Kinetic And Ligand mentioning

confidence: 99%

Section: Effect Of the Q4863a[20] Mutation On The Kinetic And Ligand mentioning

confidence: 99%

mentioning

confidence: 99%

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Residue Gln4863 within a Predicted Transmembrane Sequence of the Ca2+ Release Channel (Ryanodine Receptor) Is Critical for Ryanodine Interaction

Wang

Zhang

Bolstad

et al. 2003

Journal of Biological Chemistry

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Structural Details of the Ryanodine Receptor Calcium Release Channel and Its Gating Mechanism

Willegems

Efremov

2017

Advances in Experimental Medicine and Biology

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Ryanodine receptors (RyRs) are large intracellular calcium release channels that play a crucial role in coupling excitation to contraction in both cardiac and skeletal muscle cells. In addition, they are expressed in other cell types where their function is less well understood. Hundreds of mutations in the different isoforms of RyR have been associated with inherited myopathies and cardiac arrhythmia disorders. The structure of these important drug targets remained elusive for a long time, despite decades of intensive research. In the recent years, a technical revolution in the field of single particle cryogenic electron microscopy (SP cryo-EM) allowed solving high-resolution structures of the skeletal and cardiac RyR isoforms. Together with the structures of individual domains solved by X-ray crystallography, this resulted in an unprecedented understanding of the structure, gating and regulation of these largest known ion channels. In this chapter we describe the recently solved high-resolution structures of RyRs, discuss molecular details of the channel gating, regulation and the disease mutations. Additionally, we highlight important questions that require further progress in structural studies of RyRs.

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An antidote for calcium leak: Targeting molecular arrhythmia mechanisms

Lehnart

Lederer

2010

Journal of Molecular and Cellular Cardiology

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An Anionic Ryanoid, 10-O-succinoylryanodol, Provides Insights into the Mechanisms Governing the Interaction of Ryanoids and the Subsequent Altered Function of Ryanodine-receptor Channels

Cited by 9 publications

References 20 publications

Residue Gln4863 within a Predicted Transmembrane Sequence of the Ca2+ Release Channel (Ryanodine Receptor) Is Critical for Ryanodine Interaction

Residue Gln4863 within a Predicted Transmembrane Sequence of the Ca2+ Release Channel (Ryanodine Receptor) Is Critical for Ryanodine Interaction

Structural Details of the Ryanodine Receptor Calcium Release Channel and Its Gating Mechanism

An antidote for calcium leak: Targeting molecular arrhythmia mechanisms

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