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Identification of an amino-terminus determinant critical for ryanodine receptor/Ca(2+) release channel function

AIMS : The cardiac ryanodine receptor (RyR2), which mediates intracellular Ca(2+) release to trigger cardiomyocyte contraction, participates in development of acquired and inherited arrhythmogenic cardiac disease. This study was undertaken to characterize the network of inter- and intra-subunit inte...

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Autores principales: Seidel, Monika, de Meritens, Camille Rabesahala, Johnson, Louisa, Parthimos, Dimitris, Bannister, Mark, Thomas, Nia Lowri, Ozekhome-Mike, Esizaze, Lai, Francis Anthony, Zissimopoulos, Spyros
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898959/
https://www.ncbi.nlm.nih.gov/pubmed/32077934
http://dx.doi.org/10.1093/cvr/cvaa043
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author Seidel, Monika
de Meritens, Camille Rabesahala
Johnson, Louisa
Parthimos, Dimitris
Bannister, Mark
Thomas, Nia Lowri
Ozekhome-Mike, Esizaze
Lai, Francis Anthony
Zissimopoulos, Spyros
author_facet Seidel, Monika
de Meritens, Camille Rabesahala
Johnson, Louisa
Parthimos, Dimitris
Bannister, Mark
Thomas, Nia Lowri
Ozekhome-Mike, Esizaze
Lai, Francis Anthony
Zissimopoulos, Spyros
author_sort Seidel, Monika
collection PubMed
description AIMS : The cardiac ryanodine receptor (RyR2), which mediates intracellular Ca(2+) release to trigger cardiomyocyte contraction, participates in development of acquired and inherited arrhythmogenic cardiac disease. This study was undertaken to characterize the network of inter- and intra-subunit interactions regulating the activity of the RyR2 homotetramer. METHODS AND RESULTS : We use mutational investigations combined with biochemical assays to identify the peptide sequence bridging the β8 with β9 strand as the primary determinant mediating RyR2 N-terminus self-association. The negatively charged side chains of two aspartate residues (D179 and D180) within the β8–β9 loop are crucial for the N-terminal inter-subunit interaction. We also show that the RyR2 N-terminus domain interacts with the C-terminal channel pore region in a Ca(2+)-independent manner. The β8–β9 loop is required for efficient RyR2 subunit oligomerization but it is dispensable for N-terminus interaction with C-terminus. Deletion of the β8–β9 sequence produces unstable tetrameric channels with subdued intracellular Ca(2+) mobilization implicating a role for this domain in channel opening. The arrhythmia-linked R176Q mutation within the β8–β9 loop decreases N-terminus tetramerization but does not affect RyR2 subunit tetramerization or the N-terminus interaction with C-terminus. RyR2(R176Q) is a characteristic hypersensitive channel displaying enhanced intracellular Ca(2+) mobilization suggesting an additional role for the β8–β9 domain in channel closing. CONCLUSION : These results suggest that efficient N-terminus inter-subunit communication mediated by the β8–β9 loop may constitute a primary regulatory mechanism for both RyR2 channel activation and suppression.
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spelling pubmed-78989592021-02-25 Identification of an amino-terminus determinant critical for ryanodine receptor/Ca(2+) release channel function Seidel, Monika de Meritens, Camille Rabesahala Johnson, Louisa Parthimos, Dimitris Bannister, Mark Thomas, Nia Lowri Ozekhome-Mike, Esizaze Lai, Francis Anthony Zissimopoulos, Spyros Cardiovasc Res Original Articles AIMS : The cardiac ryanodine receptor (RyR2), which mediates intracellular Ca(2+) release to trigger cardiomyocyte contraction, participates in development of acquired and inherited arrhythmogenic cardiac disease. This study was undertaken to characterize the network of inter- and intra-subunit interactions regulating the activity of the RyR2 homotetramer. METHODS AND RESULTS : We use mutational investigations combined with biochemical assays to identify the peptide sequence bridging the β8 with β9 strand as the primary determinant mediating RyR2 N-terminus self-association. The negatively charged side chains of two aspartate residues (D179 and D180) within the β8–β9 loop are crucial for the N-terminal inter-subunit interaction. We also show that the RyR2 N-terminus domain interacts with the C-terminal channel pore region in a Ca(2+)-independent manner. The β8–β9 loop is required for efficient RyR2 subunit oligomerization but it is dispensable for N-terminus interaction with C-terminus. Deletion of the β8–β9 sequence produces unstable tetrameric channels with subdued intracellular Ca(2+) mobilization implicating a role for this domain in channel opening. The arrhythmia-linked R176Q mutation within the β8–β9 loop decreases N-terminus tetramerization but does not affect RyR2 subunit tetramerization or the N-terminus interaction with C-terminus. RyR2(R176Q) is a characteristic hypersensitive channel displaying enhanced intracellular Ca(2+) mobilization suggesting an additional role for the β8–β9 domain in channel closing. CONCLUSION : These results suggest that efficient N-terminus inter-subunit communication mediated by the β8–β9 loop may constitute a primary regulatory mechanism for both RyR2 channel activation and suppression. Oxford University Press 2020-02-20 /pmc/articles/PMC7898959/ /pubmed/32077934 http://dx.doi.org/10.1093/cvr/cvaa043 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Seidel, Monika
de Meritens, Camille Rabesahala
Johnson, Louisa
Parthimos, Dimitris
Bannister, Mark
Thomas, Nia Lowri
Ozekhome-Mike, Esizaze
Lai, Francis Anthony
Zissimopoulos, Spyros
Identification of an amino-terminus determinant critical for ryanodine receptor/Ca(2+) release channel function
title Identification of an amino-terminus determinant critical for ryanodine receptor/Ca(2+) release channel function
title_full Identification of an amino-terminus determinant critical for ryanodine receptor/Ca(2+) release channel function
title_fullStr Identification of an amino-terminus determinant critical for ryanodine receptor/Ca(2+) release channel function
title_full_unstemmed Identification of an amino-terminus determinant critical for ryanodine receptor/Ca(2+) release channel function
title_short Identification of an amino-terminus determinant critical for ryanodine receptor/Ca(2+) release channel function
title_sort identification of an amino-terminus determinant critical for ryanodine receptor/ca(2+) release channel function
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898959/
https://www.ncbi.nlm.nih.gov/pubmed/32077934
http://dx.doi.org/10.1093/cvr/cvaa043
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