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Disparate molecular mechanisms in cardiac ryanodine receptor channelopathies

Yadan Zhang, Monika Seidel, Camille Rabesahala de Meritens, Astrid Beckmann, Syeda Ahmed, Melanie Hurtz, F. Anthony Lai, Esther Zorio, Dimitris Parthimos, Spyridon Zisimopoulos Orcid Logo

Frontiers in Molecular Biosciences, Volume: 11, Start page: 1505698

Swansea University Authors: Yadan Zhang, Astrid Beckmann, Spyridon Zisimopoulos Orcid Logo

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DOI (Published version): 10.3389/fmolb.2024.1505698

Abstract

Aims: Mutations in the cardiac ryanodine receptor (RyR2) are associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). This study investigates the underlying molecular mechanisms for CPVT mutations within the RyR2 N-terminus domain (NTD). Methods and Results: We consulted the hig...

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Published in: Frontiers in Molecular Biosciences
ISSN: 2296-889X
Published: Frontiers Media SA 2024
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URI: https://cronfa.swan.ac.uk/Record/cronfa68689
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This study investigates the underlying molecular mechanisms for CPVT mutations within the RyR2 N-terminus domain (NTD). Methods and Results: We consulted the high-resolution RyR2 structure in both open and closed configuration to identify mutations G357S/R407I and A77T, which lie within the NTD intra- and inter-subunit interface with the Core Solenoid (CSol), respectively. Their structural and functional roles were compared to R169L, a mutation that lies within the NTD-NTD inter-subunit interface. Using chemical cross-linking and co-immunoprecipitation assays, we show that R169L disrupts NTD tetramerization, while it does not alter the NTD-CSol interaction. Single cell Ca2+ imaging revealed that R169L increases the number of spontaneous Ca2+ transients and the proportion of oscillating cells, while reducing the Ca2+ store content. G357S and R407I do not affect NTD tetramerization, but they also do not alter the NTD-CSol interaction. Functionally, RyR2G357S-expressing cells have Ca2+ handling properties similar to RyR2WT. A77T enhances the NTD-CSol interaction, while it does not affect NTD tetramerization. Like R169L, A77T also increases the number of spontaneous Ca2+ transients and the proportion of oscillating cells, and it reduces the Ca2+ store content. However, unlike R169L that displays Ca2+ transients of normal amplitude and shorter duration, Ca2+ transients for A77T are of smaller amplitude and normal duration. Conclusion: The NTD-CSol inter-subunit interface variant, A77T, produces a hyperactive channel by altering a different structure-function parameter to other CPVT mutations within the RyR2 NTD. Reduced NTD-NTD inter-subunit interaction and reinforced NTD inter-subunit interaction with CSol are distinct molecular mechanisms for gain-of-function RyR2 arrhythmogenic mutations.</abstract><type>Journal Article</type><journal>Frontiers in Molecular Biosciences</journal><volume>11</volume><journalNumber/><paginationStart>1505698</paginationStart><paginationEnd/><publisher>Frontiers Media SA</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic>2296-889X</issnElectronic><keywords>intracellular calcium channel, ryanodine receptor, excitation-contraction coupling, calcium cycling, arrhythmia</keywords><publishedDay>24</publishedDay><publishedMonth>12</publishedMonth><publishedYear>2024</publishedYear><publishedDate>2024-12-24</publishedDate><doi>10.3389/fmolb.2024.1505698</doi><url/><notes/><college>COLLEGE NANME</college><department>Medical School</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>MEDS</DepartmentCode><institution>Swansea University</institution><apcterm>Other</apcterm><funders>The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by a British Heart Foundation Fellowship (FS/15/30/31494) and project grant (PG/21/10657) to SZ.</funders><projectreference/><lastEdited>2025-01-13T16:15:22.1763737</lastEdited><Created>2025-01-13T15:54:06.7018844</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Biomedical Science</level></path><authors><author><firstname>Yadan</firstname><surname>Zhang</surname><orcid/><order>1</order></author><author><firstname>Monika</firstname><surname>Seidel</surname><order>2</order></author><author><firstname>Camille Rabesahala de</firstname><surname>Meritens</surname><order>3</order></author><author><firstname>Astrid</firstname><surname>Beckmann</surname><order>4</order></author><author><firstname>Syeda</firstname><surname>Ahmed</surname><order>5</order></author><author><firstname>Melanie</firstname><surname>Hurtz</surname><order>6</order></author><author><firstname>F. Anthony</firstname><surname>Lai</surname><order>7</order></author><author><firstname>Esther</firstname><surname>Zorio</surname><order>8</order></author><author><firstname>Dimitris</firstname><surname>Parthimos</surname><order>9</order></author><author><firstname>Spyridon</firstname><surname>Zisimopoulos</surname><orcid>0000-0001-5196-9450</orcid><order>10</order></author></authors><documents/><OutputDurs/></rfc1807>
spelling 2025-01-13T16:15:22.1763737 v2 68689 2025-01-13 Disparate molecular mechanisms in cardiac ryanodine receptor channelopathies 0b87eada14b5f81ff93ab9f6b30f6294 Yadan Zhang Yadan Zhang true false bdf61a354dbf27173f76fa607dfc380c Astrid Beckmann Astrid Beckmann true false ca878036edb37b3dafff6de7e9faa5e4 0000-0001-5196-9450 Spyridon Zisimopoulos Spyridon Zisimopoulos true false 2025-01-13 MEDS Aims: Mutations in the cardiac ryanodine receptor (RyR2) are associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). This study investigates the underlying molecular mechanisms for CPVT mutations within the RyR2 N-terminus domain (NTD). Methods and Results: We consulted the high-resolution RyR2 structure in both open and closed configuration to identify mutations G357S/R407I and A77T, which lie within the NTD intra- and inter-subunit interface with the Core Solenoid (CSol), respectively. Their structural and functional roles were compared to R169L, a mutation that lies within the NTD-NTD inter-subunit interface. Using chemical cross-linking and co-immunoprecipitation assays, we show that R169L disrupts NTD tetramerization, while it does not alter the NTD-CSol interaction. Single cell Ca2+ imaging revealed that R169L increases the number of spontaneous Ca2+ transients and the proportion of oscillating cells, while reducing the Ca2+ store content. G357S and R407I do not affect NTD tetramerization, but they also do not alter the NTD-CSol interaction. Functionally, RyR2G357S-expressing cells have Ca2+ handling properties similar to RyR2WT. A77T enhances the NTD-CSol interaction, while it does not affect NTD tetramerization. Like R169L, A77T also increases the number of spontaneous Ca2+ transients and the proportion of oscillating cells, and it reduces the Ca2+ store content. However, unlike R169L that displays Ca2+ transients of normal amplitude and shorter duration, Ca2+ transients for A77T are of smaller amplitude and normal duration. Conclusion: The NTD-CSol inter-subunit interface variant, A77T, produces a hyperactive channel by altering a different structure-function parameter to other CPVT mutations within the RyR2 NTD. Reduced NTD-NTD inter-subunit interaction and reinforced NTD inter-subunit interaction with CSol are distinct molecular mechanisms for gain-of-function RyR2 arrhythmogenic mutations. Journal Article Frontiers in Molecular Biosciences 11 1505698 Frontiers Media SA 2296-889X intracellular calcium channel, ryanodine receptor, excitation-contraction coupling, calcium cycling, arrhythmia 24 12 2024 2024-12-24 10.3389/fmolb.2024.1505698 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Other The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by a British Heart Foundation Fellowship (FS/15/30/31494) and project grant (PG/21/10657) to SZ. 2025-01-13T16:15:22.1763737 2025-01-13T15:54:06.7018844 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Yadan Zhang 1 Monika Seidel 2 Camille Rabesahala de Meritens 3 Astrid Beckmann 4 Syeda Ahmed 5 Melanie Hurtz 6 F. Anthony Lai 7 Esther Zorio 8 Dimitris Parthimos 9 Spyridon Zisimopoulos 0000-0001-5196-9450 10
title Disparate molecular mechanisms in cardiac ryanodine receptor channelopathies
spellingShingle Disparate molecular mechanisms in cardiac ryanodine receptor channelopathies
Yadan Zhang
Astrid Beckmann
Spyridon Zisimopoulos
title_short Disparate molecular mechanisms in cardiac ryanodine receptor channelopathies
title_full Disparate molecular mechanisms in cardiac ryanodine receptor channelopathies
title_fullStr Disparate molecular mechanisms in cardiac ryanodine receptor channelopathies
title_full_unstemmed Disparate molecular mechanisms in cardiac ryanodine receptor channelopathies
title_sort Disparate molecular mechanisms in cardiac ryanodine receptor channelopathies
author_id_str_mv 0b87eada14b5f81ff93ab9f6b30f6294
bdf61a354dbf27173f76fa607dfc380c
ca878036edb37b3dafff6de7e9faa5e4
author_id_fullname_str_mv 0b87eada14b5f81ff93ab9f6b30f6294_***_Yadan Zhang
bdf61a354dbf27173f76fa607dfc380c_***_Astrid Beckmann
ca878036edb37b3dafff6de7e9faa5e4_***_Spyridon Zisimopoulos
author Yadan Zhang
Astrid Beckmann
Spyridon Zisimopoulos
author2 Yadan Zhang
Monika Seidel
Camille Rabesahala de Meritens
Astrid Beckmann
Syeda Ahmed
Melanie Hurtz
F. Anthony Lai
Esther Zorio
Dimitris Parthimos
Spyridon Zisimopoulos
format Journal article
container_title Frontiers in Molecular Biosciences
container_volume 11
container_start_page 1505698
publishDate 2024
institution Swansea University
issn 2296-889X
doi_str_mv 10.3389/fmolb.2024.1505698
publisher Frontiers Media SA
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
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 - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 0
active_str 0
description Aims: Mutations in the cardiac ryanodine receptor (RyR2) are associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). This study investigates the underlying molecular mechanisms for CPVT mutations within the RyR2 N-terminus domain (NTD). Methods and Results: We consulted the high-resolution RyR2 structure in both open and closed configuration to identify mutations G357S/R407I and A77T, which lie within the NTD intra- and inter-subunit interface with the Core Solenoid (CSol), respectively. Their structural and functional roles were compared to R169L, a mutation that lies within the NTD-NTD inter-subunit interface. Using chemical cross-linking and co-immunoprecipitation assays, we show that R169L disrupts NTD tetramerization, while it does not alter the NTD-CSol interaction. Single cell Ca2+ imaging revealed that R169L increases the number of spontaneous Ca2+ transients and the proportion of oscillating cells, while reducing the Ca2+ store content. G357S and R407I do not affect NTD tetramerization, but they also do not alter the NTD-CSol interaction. Functionally, RyR2G357S-expressing cells have Ca2+ handling properties similar to RyR2WT. A77T enhances the NTD-CSol interaction, while it does not affect NTD tetramerization. Like R169L, A77T also increases the number of spontaneous Ca2+ transients and the proportion of oscillating cells, and it reduces the Ca2+ store content. However, unlike R169L that displays Ca2+ transients of normal amplitude and shorter duration, Ca2+ transients for A77T are of smaller amplitude and normal duration. Conclusion: The NTD-CSol inter-subunit interface variant, A77T, produces a hyperactive channel by altering a different structure-function parameter to other CPVT mutations within the RyR2 NTD. Reduced NTD-NTD inter-subunit interaction and reinforced NTD inter-subunit interaction with CSol are distinct molecular mechanisms for gain-of-function RyR2 arrhythmogenic mutations.
published_date 2024-12-24T08:37:32Z
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score 11.364387

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