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Structural Components of Ryanodine Responsible for Modulation of Sarcoplasmic Reticulum Calcium Channel Function

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Department of Biochemistry and Department of Pharmacology, University of Nevada, Reno, Nevada 89557, Cardiac Medicine, National Heart and Lung Institute, Imperial College, University of London, Dovehouse Street, London SW3 6LY, United Kingdom, Département de chimie, Université de Sherbrooke, Sherbrooke, Québec J1K2R1, Canada, and Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana 46202-5120
Cite this: Biochemistry 1997, 36, 10, 2939–2950
Publication Date (Web):March 11, 1997
https://doi.org/10.1021/bi9623901
Copyright © 1997 American Chemical Society

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    Abstract

    Comparative molecular field analysis (CoMFA) was used to analyze the relationship between the structure of a group of ryanoids and the modulation of the calcium channel function of the ryanodine receptor. The conductance properties of ryanodine receptors purified from sheep heart were measured using the planar, lipid bilayer technique. The magnitude of the ryanoid-induced fractional conductance was strongly correlated to specific structural loci on the ligand. Briefly, electrostatic effects were more prominent than steric effects. The 10-position of the ryanoid had the greatest influence on fractional conductance. Different regions of the ligand have opposing effects on fractional conductance. For example, steric bulk at the 10-position is correlated with decreased fractional conductance, whereas steric bulk at the 2-position (isopropyl position) is correlated with increased fractional conductance. In contrast to fractional conductance, the 3-position (the pyrrole locus) had the greatest influence on ligand binding, whereas the 10-position had comparatively little influence on binding. Two possible models of ryanodine action, a direct (or channel plug) mechanism and an allosteric mechanism, were examined in light of the CoMFA. Taken together, the data do not appear to be consistent with direct interaction between ryanodine and the translocating ion. The data appear to be more consistent with an allosteric mechanism. It is suggested the ryanoids act by inducing or stabilizing a conformational change in the ryanodine receptor that results in the observed alterations in cation conductance.

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     This work was supported by the American Heart Association (93012790), the National Science Foundation (MCB-9317684), The University of Nevada Molecular Modeling/Graphics Core Facility, the Glaxo Cardiac Discovery Program, The Wellcome Trust, the British Heart Foundation, and the Showalter Trust.

    *

     Corresponding author Phone:  702-784-4102. Fax:  702-784-1419. E-mail:  [email protected].

     Department of Biochemistry, University of Nevada.

    §

     University of London.

     Université de Sherbrooke.

     Indiana University School of Medicine.

     Department of Pharmacology, University of Nevada.

     Abstract published in Advance ACS Abstracts, March 1, 1997.

    Cited By

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    2. Amédée des Georges, Oliver B. Clarke, Ran Zalk, Qi Yuan, Kendall J. Condon, Robert A. Grassucci, Wayne A. Hendrickson, Andrew R. Marks, Joachim Frank. Structural Basis for Gating and Activation of RyR1. Cell 2016, 167 (1) , 145-157.e17. https://doi.org/10.1016/j.cell.2016.08.075
    3. Kangway V. Chuang, Chen Xu, Sarah E. Reisman. A 15-step synthesis of (+)-ryanodol. Science 2016, 353 (6302) , 912-915. https://doi.org/10.1126/science.aag1028
    4. Oliver B Clarke, Wayne A Hendrickson. Structures of the colossal RyR1 calcium release channel. Current Opinion in Structural Biology 2016, 39 , 144-152. https://doi.org/10.1016/j.sbi.2016.09.002
    5. Saptarshi Mukherjee, N. Lowri Thomas, Alan J. Williams. Insights into the Gating Mechanism of the Ryanodine-Modified Human Cardiac Ca 2+ -Release Channel (Ryanodine Receptor 2). Molecular Pharmacology 2014, 86 (3) , 318-329. https://doi.org/10.1124/mol.114.093757
    6. Peter Lümmen. Calcium Channels as Molecular Target Sites of Novel Insecticides. 2013, 287-347. https://doi.org/10.1016/B978-0-12-394389-7.00005-3
    7. Nia L. Thomas, Alan J. Williams. Pharmacology of ryanodine receptors and Ca 2+ ‐induced Ca 2+ release. Wiley Interdisciplinary Reviews: Membrane Transport and Signaling 2012, 1 (4) , 383-397. https://doi.org/10.1002/wmts.34
    8. Kishani M. Ranatunga, S. R. Wayne Chen, Luc Ruest, William Welch, Alan J. Williams. Quantification of the effects of a ryanodine receptor channel mutation on interaction with a ryanoid. Molecular Membrane Biology 2007, 24 (3) , 185-193. https://doi.org/10.1080/09687860601076522
    9. Bhavna Tanna, William Welch, Luc Ruest, John L. Sutko, Alan J. Williams. The Interaction of an Impermeant Cation with the Sheep Cardiac RyR Channel Alters Ryanoid Association. Molecular Pharmacology 2006, 69 (6) , 1990-1997. https://doi.org/10.1124/mol.105.021659
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    11. Angela F. Dulhunty, Pierre Pouliquin, Marjorie Coggan, Peter W. Gage, Philip G. Board. A recently identified member of the glutathione transferase structural family modifies cardiac RyR2 substate activity, coupled gating and activation by Ca2+ and ATP. Biochemical Journal 2005, 390 (1) , 333-343. https://doi.org/10.1042/BJ20042113
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    13. Montserrat Samsó, Terence Wagenknecht, P D Allen. Internal structure and visualization of transmembrane domains of the RyR1 calcium release channel by cryo-EM. Nature Structural & Molecular Biology 2005, 12 (6) , 539-544. https://doi.org/10.1038/nsmb938
    14. Bhavna Tanna, William Welch, Luc Ruest, John L. Sutko, Alan J. Williams. Voltage-Sensitive Equilibrium between Two States within a Ryanoid-Modified Conductance State of the Ryanodine Receptor Channel. Biophysical Journal 2005, 88 (4) , 2585-2596. https://doi.org/10.1529/biophysj.104.048587
    15. Régent Laporte, Adrian Hui, Ismail Laher. Pharmacological Modulation of Sarcoplasmic Reticulum Function in Smooth Muscle. Pharmacological Reviews 2004, 56 (4) , 439-513. https://doi.org/10.1124/pr.56.4.1
    16. Bhavna Tanna, William Welch, Luc Ruest, John L. Sutko, Alan J. Williams. 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. The Journal of General Physiology 2003, 121 (6) , 551-561. https://doi.org/10.1085/jgp.200208753
    17. S.R. Wayne Chen, Pin Li, Mingcai Zhao, Xiaoli Li, Lin Zhang. Role of the Proposed Pore-Forming Segment of the Ca2+ Release Channel (Ryanodine Receptor) in Ryanodine Interaction*. Biophysical Journal 2002, 82 (5) , 2436-2447. https://doi.org/10.1016/S0006-3495(02)75587-2
    18. Robert G. Tsushima, James E. Kelly, J. Andrew Wasserstrom. Subconductance Activity Induced by Quinidine and Quinidinium in Purified Cardiac Sarcoplasmic Reticulum Calcium Release Channels. Journal of Pharmacology and Experimental Therapeutics 2002, 301 (2) , 729-737. https://doi.org/10.1124/jpet.301.2.729
    19. Luc Ruest, Marco Dodier, Hélène De Sève, Christian Lessard, Pascal Mongrain. Ryanoids and related compounds Isolation and characterization of 11 new minor ryanoids from the plant Ryania Speciosa Vahl. Canadian Journal of Chemistry 2002, 80 (5) , 483-488. https://doi.org/10.1139/v02-048
    20. Bhavna Tanna, William Welch, Luc Ruest, John L Sutko, Alan J Williams. Excess noise in modified conductance states following the interaction of ryanoids with cardiac ryanodine receptor channels. FEBS Letters 2002, 516 (1-3) , 35-39. https://doi.org/10.1016/S0014-5793(02)02462-6
    21. G. G. Du, X. Guo, V. K. Khanna, D. H. MacLennan. 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 2001, 98 (24) , 13625-13630. https://doi.org/10.1073/pnas.241516898
    22. Don-On Daniel Mak, Sean McBride, J. Kevin Foskett. Regulation by Ca2+ and Inositol 1,4,5-Trisphosphate (Insp3) of Single Recombinant Type 3 Insp3 Receptor Channels. The Journal of General Physiology 2001, 117 (5) , 435-446. https://doi.org/10.1085/jgp.117.5.435
    23. Bhavna Tanna, William Welch, Luc Ruest, John L. Sutko, Alan J. Williams. Ryanoid Modification of the Cardiac Muscle Ryanodine Receptor Channel Results in Relocation of the Tetraethylammonium Binding Site. The Journal of General Physiology 2001, 117 (5) , 385-394. https://doi.org/10.1085/jgp.117.5.385
    24. James D. Fessenden, Lili Chen, Yaming Wang, Cecilia Paolini, Clara Franzini-Armstrong, Paul D. Allen, Isaac N. Pessah. Ryanodine receptor point mutant E4032A reveals an allosteric interaction with ryanodine. Proceedings of the National Academy of Sciences 2001, 98 (5) , 2865-2870. https://doi.org/10.1073/pnas.041608898
    25. Bhavna Tanna, William Welch, Luc Ruest, John L. Sutko, Alan J. Williams. The Interaction of a Neutral Ryanoid with the Ryanodine Receptor Channel Provides Insights into the Mechanisms by Which Ryanoid Binding Is Modulated by Voltage. The Journal of General Physiology 2000, 116 (1) , 1-10. https://doi.org/10.1085/jgp.116.1.1
    26. Xuehong Xu, Manjunatha B. Bhat, Miyuki Nishi, Hiroshi Takeshima, Jianjie Ma. Molecular Cloning of cDNA Encoding a Drosophila Ryanodine Receptor and Functional Studies of the Carboxyl-Terminal Calcium Release Channel. Biophysical Journal 2000, 78 (3) , 1270-1281. https://doi.org/10.1016/S0006-3495(00)76683-5
    27. Stephen L Gaffin. Simplified calcium transport and storage pathways. Journal of Thermal Biology 1999, 24 (4) , 251-264. https://doi.org/10.1016/S0306-4565(99)00020-0
    28. Bhavna Tanna, William Welch, Luc Ruest, John L. Sutko, Alan J. Williams. Interactions of a Reversible Ryanoid (21-Amino-9α-Hydroxy-Ryanodine) with Single Sheep Cardiac Ryanodine Receptor Channels. The Journal of General Physiology 1998, 112 (1) , 55-69. https://doi.org/10.1085/jgp.112.1.55
    29. Keshore R. Bidasee, Henry R. Besch. Structure-Function Relationships among Ryanodine Derivatives. Journal of Biological Chemistry 1998, 273 (20) , 12176-12186. https://doi.org/10.1074/jbc.273.20.12176

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