Molecular, Subcellular, and Arrhythmogenic Mechanisms in Genetic RyR2 Disease

Fowler, Ewan Douglas; Zisimopoulos, Spyridon

doi:10.3390/biom12081030

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Molecular, Subcellular, and Arrhythmogenic Mechanisms in Genetic RyR2 Disease

Ewan Douglas Fowler

, Spyridon Zisimopoulos

Biomolecules, Volume: 12, Issue: 8, Start page: 1030

Swansea University Author: Spyridon Zisimopoulos

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DOI (Published version): 10.3390/biom12081030

Abstract

AbstractThe ryanodine receptor (RyR2) has a critical role in controlling Ca2+ release from the sarcoplasmic reticulum (SR) throughout the cardiac cycle. RyR2 protein has multiple functional domains with specific roles, and four of these RyR2 protomers are required to form the quaternary structure th...

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Published in:	Biomolecules
ISSN:	2218-273X
Published:	MDPI AG 2022
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URI:	https://cronfa.swan.ac.uk/Record/cronfa62164
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first_indexed	2022-12-13T18:41:26Z
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spelling	2022-12-30T13:48:11.0495554 v2 62164 2022-12-13 Molecular, Subcellular, and Arrhythmogenic Mechanisms in Genetic RyR2 Disease ca878036edb37b3dafff6de7e9faa5e4 0000-0001-5196-9450 Spyridon Zisimopoulos Spyridon Zisimopoulos true false 2022-12-13 BMS AbstractThe ryanodine receptor (RyR2) has a critical role in controlling Ca2+ release from the sarcoplasmic reticulum (SR) throughout the cardiac cycle. RyR2 protein has multiple functional domains with specific roles, and four of these RyR2 protomers are required to form the quaternary structure that comprises the functional channel. Numerous mutations in the gene encoding RyR2 protein have been identified and many are linked to a wide spectrum of arrhythmic heart disease. Gain of function mutations (GoF) result in a hyperactive channel that causes excessive spontaneous SR Ca2+ release. This is the predominant cause of the inherited syndrome catecholaminergic polymorphic ventricular tachycardia (CPVT). Recently, rare hypoactive loss of function (LoF) mutations have been identified that produce atypical effects on cardiac Ca2+ handling that has been termed calcium release deficiency syndrome (CRDS). Aberrant Ca2+ release resulting from both GoF and LoF mutations can result in arrhythmias through the Na+/Ca2+ exchange mechanism. This mini-review discusses recent findings regarding the role of RyR2 domains and endogenous regulators that influence RyR2 gating normally and with GoF/LoF mutations. The arrhythmogenic consequences of GoF/LoF mutations will then be discussed at the macromolecular and cellular level. Journal Article Biomolecules 12 8 1030 MDPI AG 2218-273X ryanodine receptor; catecholaminergic polymorphic ventricular tachycardia; calcium release deficiency syndrome; delayed afterdepolarizations; early afterdepolarizations; calcium sparks; long QT syndrome; arrhythmias 26 7 2022 2022-07-26 10.3390/biom12081030 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University E.D.F. was supported by funding from the British Heart Foundation, grant number FS/IBSRF/21/25071. S.Z. was supported by funding from the British Heart Foundation, grant number PG/21/10657. 2022-12-30T13:48:11.0495554 2022-12-13T18:33:57.9819032 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Ewan Douglas Fowler 0000-0001-5580-2156 1 Spyridon Zisimopoulos 0000-0001-5196-9450 2 62164__26075__bd39072f39f847348de92d15a1f339c5.pdf Fowler & Zissimopoulos_Biomolecules_2022.pdf 2022-12-13T18:36:15.3253814 Output 1912751 application/pdf Version of Record true © 2022 by the authors. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license true eng https://creativecommons.org/licenses/by/4.0/
title	Molecular, Subcellular, and Arrhythmogenic Mechanisms in Genetic RyR2 Disease
spellingShingle	Molecular, Subcellular, and Arrhythmogenic Mechanisms in Genetic RyR2 Disease Spyridon Zisimopoulos
title_short	Molecular, Subcellular, and Arrhythmogenic Mechanisms in Genetic RyR2 Disease
title_full	Molecular, Subcellular, and Arrhythmogenic Mechanisms in Genetic RyR2 Disease
title_fullStr	Molecular, Subcellular, and Arrhythmogenic Mechanisms in Genetic RyR2 Disease
title_full_unstemmed	Molecular, Subcellular, and Arrhythmogenic Mechanisms in Genetic RyR2 Disease
title_sort	Molecular, Subcellular, and Arrhythmogenic Mechanisms in Genetic RyR2 Disease
author_id_str_mv	ca878036edb37b3dafff6de7e9faa5e4
author_id_fullname_str_mv	ca878036edb37b3dafff6de7e9faa5e4_***_Spyridon Zisimopoulos
author	Spyridon Zisimopoulos
author2	Ewan Douglas Fowler Spyridon Zisimopoulos
format	Journal article
container_title	Biomolecules
container_volume	12
container_issue	8
container_start_page	1030
publishDate	2022
institution	Swansea University
issn	2218-273X
doi_str_mv	10.3390/biom12081030
publisher	MDPI AG
college_str	Faculty of Medicine, Health and Life Sciences
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hierarchy_top_title	Faculty of Medicine, Health and Life Sciences
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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	AbstractThe ryanodine receptor (RyR2) has a critical role in controlling Ca2+ release from the sarcoplasmic reticulum (SR) throughout the cardiac cycle. RyR2 protein has multiple functional domains with specific roles, and four of these RyR2 protomers are required to form the quaternary structure that comprises the functional channel. Numerous mutations in the gene encoding RyR2 protein have been identified and many are linked to a wide spectrum of arrhythmic heart disease. Gain of function mutations (GoF) result in a hyperactive channel that causes excessive spontaneous SR Ca2+ release. This is the predominant cause of the inherited syndrome catecholaminergic polymorphic ventricular tachycardia (CPVT). Recently, rare hypoactive loss of function (LoF) mutations have been identified that produce atypical effects on cardiac Ca2+ handling that has been termed calcium release deficiency syndrome (CRDS). Aberrant Ca2+ release resulting from both GoF and LoF mutations can result in arrhythmias through the Na+/Ca2+ exchange mechanism. This mini-review discusses recent findings regarding the role of RyR2 domains and endogenous regulators that influence RyR2 gating normally and with GoF/LoF mutations. The arrhythmogenic consequences of GoF/LoF mutations will then be discussed at the macromolecular and cellular level.
published_date	2022-07-26T04:21:34Z
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Molecular, Subcellular, and Arrhythmogenic Mechanisms in Genetic RyR2 Disease

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