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Structural analyses of human ryanodine receptor type 2 channels reveal the mechanisms for sudden cardiac death and treatment.
<div class='caption-title'>Cryo-EM reconstructions of human RyR2 showing that the CPVT mutant RyR2-R2474S puts the channel into the primed state, and treatment with the Rycal ARM210 and CaM puts the channel back toward the closed state.</div>
<div class='caption-title'>Stabilization of RyR2-R2474S by the Rycal ARM210.</div>
Miotto MC, Weninger G, Dridi H, Yuan Q, Liu Y, Wronska A, Melville Z, Sittenfeld L, Reiken S, Marks AR
OpenAccess logo Sci Adv 8 eabo1272 (2022)
Related entries: 7u9q, 7u9r, 7u9t, 7u9x, 7ua1, 7ua3, 7ua4, 7ua5, 7ua9

Cited: 14 times
EuropePMC logo PMID: 35857850

Abstract

Ryanodine receptor type 2 (RyR2) mutations have been linked to an inherited form of exercise-induced sudden cardiac death called catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT results from stress-induced sarcoplasmic reticular Ca2+ leak via the mutant RyR2 channels during diastole. We present atomic models of human wild-type (WT) RyR2 and the CPVT mutant RyR2-R2474S determined by cryo-electron microscopy with overall resolutions in the range of 2.6 to 3.6 Å, and reaching local resolutions of 2.25 Å, unprecedented for RyR2 channels. Under nonactivating conditions, the RyR2-R2474S channel is in a "primed" state between the closed and open states of WT RyR2, rendering it more sensitive to activation that results in stress-induced Ca2+ leak. The Rycal drug ARM210 binds to RyR2-R2474S, reverting the primed state toward the closed state. Together, these studies provide a mechanism for CPVT and for the therapeutic actions of ARM210.

Articles - 7u9z mentioned but not cited (1)

  1. Structural analyses of human ryanodine receptor type 2 channels reveal the mechanisms for sudden cardiac death and treatment. Miotto MC, Weninger G, Dridi H, Yuan Q, Liu Y, Wronska A, Melville Z, Sittenfeld L, Reiken S, Marks AR. Sci Adv 8 eabo1272 (2022)


Reviews citing this publication (3)

  1. Three-dimensional perspective on ryanodine receptor mutations causing skeletal and cardiac muscle-related diseases. Iyer KA, Barnakov V, Samsó M. Curr Opin Pharmacol 68 102327 (2023)
  2. Mitochondrial Calcium Overload Plays a Causal Role in Oxidative Stress in the Failing Heart. Dridi H, Santulli G, Bahlouli L, Miotto MC, Weninger G, Marks AR. Biomolecules 13 1409 (2023)
  3. Targeting ryanodine receptors to treat human diseases. Marks AR. J Clin Invest 133 e162891 (2023)

Articles citing this publication (10)

  1. Citrullination is linked to reduced Ca2+ sensitivity in hearts of a murine model of rheumatoid arthritis. Pironti G, Gastaldello S, Rassier DE, Lanner JT, Carlström M, Lund LH, Westerblad H, Yamada T, Andersson DC. Acta Physiol (Oxf) 236 e13869 (2022)
  2. 1,4-Benzothiazepines with Cyclopropanol Groups and Their Structural Analogues Exhibit Both RyR2-Stabilizing and SERCA2a-Stimulating Activities. Mitronova GY, Quentin C, Belov VN, Wegener JW, Kiszka KA, Lehnart SE. J Med Chem 66 15761-15775 (2023)
  3. A dual-targeted drug inhibits cardiac ryanodine receptor Ca2+ leak but activates SERCA2a Ca2+ uptake. Wegener JW, Mitronova GY, ElShareif L, Quentin C, Belov V, Pochechueva T, Hasenfuss G, Ackermann L, Lehnart SE. Life Sci Alliance 7 e202302278 (2024)
  4. Allosteric modulation of ryanodine receptor RyR1 by nucleotide derivatives. Cholak S, Saville JW, Zhu X, Berezuk AM, Tuttle KS, Haji-Ghassemi O, Alvarado FJ, Van Petegem F, Subramaniam S. Structure 31 790-800.e4 (2023)
  5. Arrhythmogenic mechanism of a novel ryanodine receptor mutation underlying sudden cardiac death. Qian Y, Zuo D, Xiong J, Yin Y, Qi R, Ma X, Yan A, Yang Y, Liu P, Zhang J, Tang K, Peng W, Xu Y, Liu Z. Europace 25 euad220 (2023)
  6. Cysteines 1078 and 2991 cross-linking plays a critical role in redox regulation of cardiac ryanodine receptor (RyR). Nikolaienko R, Bovo E, Kahn D, Gracia R, Jamrozik T, Zima AV. Nat Commun 14 4498 (2023)
  7. Heart failure-induced cognitive dysfunction is mediated by intracellular Ca2+ leak through ryanodine receptor type 2. Dridi H, Liu Y, Reiken S, Liu X, Argyrousi EK, Yuan Q, Miotto MC, Sittenfeld L, Meddar A, Soni RK, Arancio O, Lacampagne A, Marks AR. Nat Neurosci 26 1365-1378 (2023)
  8. Location, location, and activation of a channel by calcium. Kuo IY, Ehrlich BE. Proc Natl Acad Sci U S A 119 e2214826119 (2022)
  9. Molecular Aspects Implicated in Dantrolene Selectivity with Respect to Ryanodine Receptor Isoforms. Gaburjakova J, Gaburjakova M. Int J Mol Sci 24 5409 (2023)
  10. Personalized medicine in the dish to prevent calcium leak associated with short-coupled polymorphic ventricular tachycardia in patient-derived cardiomyocytes. Sleiman Y, Reiken S, Charrabi A, Jaffré F, Sittenfeld LR, Pasquié JL, Colombani S, Lerman BB, Chen S, Marks AR, Cheung JW, Evans T, Lacampagne A, Meli AC. Stem Cell Res Ther 14 266 (2023)


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