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Defective ryanodine receptor N-terminus inter-subunit interaction is a common mechanism in neuromuscular and cardiac disorders

YADAN ZHANG, Camille Rabesahala de Meritens, Astrid Beckmann, F. Anthony Lai, Spyridon Zisimopoulos Orcid Logo

Frontiers in Physiology, Volume: 13

Swansea University Authors: YADAN ZHANG, Camille Rabesahala de Meritens, Astrid Beckmann, Spyridon Zisimopoulos Orcid Logo

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Abstract

The ryanodine receptor (RyR) is a homotetrameric channel mediating sarcoplasmic reticulum Ca2+ release required for skeletal and cardiac muscle contraction. Mutations in RyR1 and RyR2 lead to life-threatening malignant hyperthermia episodes and ventricular tachycardia, respectively. In this brief re...

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Published in: Frontiers in Physiology
ISSN: 1664-042X
Published: Frontiers Media SA 2022
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa62166
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Abstract: The ryanodine receptor (RyR) is a homotetrameric channel mediating sarcoplasmic reticulum Ca2+ release required for skeletal and cardiac muscle contraction. Mutations in RyR1 and RyR2 lead to life-threatening malignant hyperthermia episodes and ventricular tachycardia, respectively. In this brief report, we use chemical cross-linking to demonstrate that pathogenic RyR1 R163C and RyR2 R169Q mutations reduce N-terminus domain (NTD) tetramerization. Introduction of positively-charged residues (Q168R, M399R) in the NTD-NTD inter-subunit interface normalizes RyR2-R169Q NTD tetramerization. These results indicate that perturbation of NTD-NTD inter-subunit interactions is an underlying molecular mechanism in both RyR1 and RyR2 pathophysiology. Importantly, our data provide proof of concept that stabilization of this critical RyR1/2 structure-function parameter offers clear therapeutic potential.
Keywords: amino-terminus, catecholaminergic polymorphic ventricular tachycardia, malignant hyperthermia, inter-subunit interaction, tetramerization, ryanodine receptor (RyR)
College: Faculty of Medicine, Health and Life Sciences
Funders: This work was supported by a British Heart Foundation Fellowship (FS/15/30/31494) and project grant to SZ (PG/21/10657).