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Function of a mutant ryanodine receptor (T4709M) linked to congenital myopathy
Physiological muscle contraction requires an intact ligand gating mechanism of the ryanodine receptor 1 (RyR1), the Ca(2+)-release channel of the sarcoplasmic reticulum. Some mutations impair the gating and thus cause muscle disease. The RyR1 mutation T4706M is linked to a myopathy characterized by...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10480487/ https://www.ncbi.nlm.nih.gov/pubmed/37670077 http://dx.doi.org/10.1038/s41598-023-41801-2 |
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author | Magyar, Zsuzsanna É. Hevesi, Judit Groom, Linda Dirksen, Robert T. Almássy, János |
author_facet | Magyar, Zsuzsanna É. Hevesi, Judit Groom, Linda Dirksen, Robert T. Almássy, János |
author_sort | Magyar, Zsuzsanna É. |
collection | PubMed |
description | Physiological muscle contraction requires an intact ligand gating mechanism of the ryanodine receptor 1 (RyR1), the Ca(2+)-release channel of the sarcoplasmic reticulum. Some mutations impair the gating and thus cause muscle disease. The RyR1 mutation T4706M is linked to a myopathy characterized by muscle weakness. Although, low expression of the T4706M RyR1 protein can explain in part the symptoms, little is known about the function RyR1 channels with this mutation. In order to learn whether this mutation alters channel function in a manner that can account for the observed symptoms, we examined RyR1 channels isolated from mice homozygous for the T4709M (TM) mutation at the single channel level. Ligands, including Ca(2+), ATP, Mg(2+) and the RyR inhibitor dantrolene were tested. The full conductance of the TM channel was the same as that of wild type (wt) channels and a population of partial open (subconductive) states were not observed. However, two unique sub-populations of TM RyRs were identified. One half of the TM channels exhibited high open probability at low (100 nM) and high (50 μM) cytoplasmic [Ca(2+)], resulting in Ca(2+)-insensitive, constitutively high P(o) channels. The rest of the TM channels exhibited significantly lower activity within the physiologically relevant range of cytoplasmic [Ca(2+)], compared to wt. TM channels retained normal Mg(2+) block, modulation by ATP, and inhibition by dantrolene. Together, these results suggest that the TM mutation results in a combination of primary and secondary RyR1 dysfunctions that contribute to disease pathogenesis. |
format | Online Article Text |
id | pubmed-10480487 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-104804872023-09-07 Function of a mutant ryanodine receptor (T4709M) linked to congenital myopathy Magyar, Zsuzsanna É. Hevesi, Judit Groom, Linda Dirksen, Robert T. Almássy, János Sci Rep Article Physiological muscle contraction requires an intact ligand gating mechanism of the ryanodine receptor 1 (RyR1), the Ca(2+)-release channel of the sarcoplasmic reticulum. Some mutations impair the gating and thus cause muscle disease. The RyR1 mutation T4706M is linked to a myopathy characterized by muscle weakness. Although, low expression of the T4706M RyR1 protein can explain in part the symptoms, little is known about the function RyR1 channels with this mutation. In order to learn whether this mutation alters channel function in a manner that can account for the observed symptoms, we examined RyR1 channels isolated from mice homozygous for the T4709M (TM) mutation at the single channel level. Ligands, including Ca(2+), ATP, Mg(2+) and the RyR inhibitor dantrolene were tested. The full conductance of the TM channel was the same as that of wild type (wt) channels and a population of partial open (subconductive) states were not observed. However, two unique sub-populations of TM RyRs were identified. One half of the TM channels exhibited high open probability at low (100 nM) and high (50 μM) cytoplasmic [Ca(2+)], resulting in Ca(2+)-insensitive, constitutively high P(o) channels. The rest of the TM channels exhibited significantly lower activity within the physiologically relevant range of cytoplasmic [Ca(2+)], compared to wt. TM channels retained normal Mg(2+) block, modulation by ATP, and inhibition by dantrolene. Together, these results suggest that the TM mutation results in a combination of primary and secondary RyR1 dysfunctions that contribute to disease pathogenesis. Nature Publishing Group UK 2023-09-05 /pmc/articles/PMC10480487/ /pubmed/37670077 http://dx.doi.org/10.1038/s41598-023-41801-2 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Magyar, Zsuzsanna É. Hevesi, Judit Groom, Linda Dirksen, Robert T. Almássy, János Function of a mutant ryanodine receptor (T4709M) linked to congenital myopathy |
title | Function of a mutant ryanodine receptor (T4709M) linked to congenital myopathy |
title_full | Function of a mutant ryanodine receptor (T4709M) linked to congenital myopathy |
title_fullStr | Function of a mutant ryanodine receptor (T4709M) linked to congenital myopathy |
title_full_unstemmed | Function of a mutant ryanodine receptor (T4709M) linked to congenital myopathy |
title_short | Function of a mutant ryanodine receptor (T4709M) linked to congenital myopathy |
title_sort | function of a mutant ryanodine receptor (t4709m) linked to congenital myopathy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10480487/ https://www.ncbi.nlm.nih.gov/pubmed/37670077 http://dx.doi.org/10.1038/s41598-023-41801-2 |
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