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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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DOI (Published version): 10.3389/fphys.2022.1032132

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
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URI: https://cronfa.swan.ac.uk/Record/cronfa62166
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spelling 2022-12-30T13:44:41.9329062 v2 62166 2022-12-13 Defective ryanodine receptor N-terminus inter-subunit interaction is a common mechanism in neuromuscular and cardiac disorders 0b87eada14b5f81ff93ab9f6b30f6294 YADAN ZHANG YADAN ZHANG true false 7b31f44f4700852824f9a3cdc3ee0533 Camille Rabesahala de Meritens Camille Rabesahala de Meritens true false bdf61a354dbf27173f76fa607dfc380c Astrid Beckmann Astrid Beckmann true false ca878036edb37b3dafff6de7e9faa5e4 0000-0001-5196-9450 Spyridon Zisimopoulos Spyridon Zisimopoulos true false 2022-12-13 BMS 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. Journal Article Frontiers in Physiology 13 Frontiers Media SA 1664-042X amino-terminus, catecholaminergic polymorphic ventricular tachycardia, malignant hyperthermia, inter-subunit interaction, tetramerization, ryanodine receptor (RyR) 12 10 2022 2022-10-12 10.3389/fphys.2022.1032132 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University This work was supported by a British Heart Foundation Fellowship (FS/15/30/31494) and project grant to SZ (PG/21/10657). 2022-12-30T13:44:41.9329062 2022-12-13T18:45:54.1026424 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine YADAN ZHANG 1 Camille Rabesahala de Meritens 2 Astrid Beckmann 3 F. Anthony Lai 4 Spyridon Zisimopoulos 0000-0001-5196-9450 5 62166__26076__eb0de3f9715b4f2eb70c666abe0da904.pdf Zhang et al_Front Physiol_2022.pdf 2022-12-13T18:46:52.7122827 Output 1107488 application/pdf Version of Record true © 2022 Zhang, Rabesahala de Meritens, Beckmann, Lai and Zissimopoulos. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) true eng https://creativecommons.org/licenses/by/4.0/
title Defective ryanodine receptor N-terminus inter-subunit interaction is a common mechanism in neuromuscular and cardiac disorders
spellingShingle 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
Spyridon Zisimopoulos
title_short Defective ryanodine receptor N-terminus inter-subunit interaction is a common mechanism in neuromuscular and cardiac disorders
title_full Defective ryanodine receptor N-terminus inter-subunit interaction is a common mechanism in neuromuscular and cardiac disorders
title_fullStr Defective ryanodine receptor N-terminus inter-subunit interaction is a common mechanism in neuromuscular and cardiac disorders
title_full_unstemmed Defective ryanodine receptor N-terminus inter-subunit interaction is a common mechanism in neuromuscular and cardiac disorders
title_sort Defective ryanodine receptor N-terminus inter-subunit interaction is a common mechanism in neuromuscular and cardiac disorders
author_id_str_mv 0b87eada14b5f81ff93ab9f6b30f6294
7b31f44f4700852824f9a3cdc3ee0533
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ca878036edb37b3dafff6de7e9faa5e4
author_id_fullname_str_mv 0b87eada14b5f81ff93ab9f6b30f6294_***_YADAN ZHANG
7b31f44f4700852824f9a3cdc3ee0533_***_Camille Rabesahala de Meritens
bdf61a354dbf27173f76fa607dfc380c_***_Astrid Beckmann
ca878036edb37b3dafff6de7e9faa5e4_***_Spyridon Zisimopoulos
author YADAN ZHANG
Camille Rabesahala de Meritens
Astrid Beckmann
Spyridon Zisimopoulos
author2 YADAN ZHANG
Camille Rabesahala de Meritens
Astrid Beckmann
F. Anthony Lai
Spyridon Zisimopoulos
format Journal article
container_title Frontiers in Physiology
container_volume 13
publishDate 2022
institution Swansea University
issn 1664-042X
doi_str_mv 10.3389/fphys.2022.1032132
publisher Frontiers Media SA
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
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description 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.
published_date 2022-10-12T04:21:35Z
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