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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, 7u9z, 7ua1, 7ua3, 7ua4, 7ua5, 7ua9

Cited: 18 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.

Reviews - 7u9x mentioned but not cited (2)

  1. Targeting ryanodine receptors to treat human diseases. Marks AR. J Clin Invest 133 e162891 (2023)
  2. Impaired Cardiomyocyte Maturation Leading to DCM: A Case Report and Literature Review. Zhou L, Huang J, Li H, Duan H, Hua Y, Guo Y, Zhou K, Li Y. Medicina (Kaunas) 59 1158 (2023)

Articles - 7u9x mentioned but not cited (1)



Reviews citing this publication (2)

  1. 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)
  2. 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)

Articles citing this publication (13)



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