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Calcineurin Controls Voltage-Dependent-Inactivation (VDI) of the Normal and Timothy Cardiac Channels
Ca(2+)-entry in the heart is tightly controlled by Cav1.2 inactivation, which involves Ca(2+)-dependent inactivation (CDI) and voltage-dependent inactivation (VDI) components. Timothy syndrome, a subtype-form of congenital long-QT syndrome, results from a nearly complete elimination of VDI by the G4...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3328044/ https://www.ncbi.nlm.nih.gov/pubmed/22511998 http://dx.doi.org/10.1038/srep00366 |
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author | Cohen-Kutner, Moshe Yahalom, Yfat Trus, Michael Atlas, Daphne |
author_facet | Cohen-Kutner, Moshe Yahalom, Yfat Trus, Michael Atlas, Daphne |
author_sort | Cohen-Kutner, Moshe |
collection | PubMed |
description | Ca(2+)-entry in the heart is tightly controlled by Cav1.2 inactivation, which involves Ca(2+)-dependent inactivation (CDI) and voltage-dependent inactivation (VDI) components. Timothy syndrome, a subtype-form of congenital long-QT syndrome, results from a nearly complete elimination of VDI by the G406R mutation in the α(1)1.2 subunit of Cav1.2. Here, we show that a single (A1929P) or a double mutation (H1926A-H1927A) within the CaN-binding site at the human C-terminal tail of α(1)1.2, accelerate the inactivation rate and enhances VDI of both wt and Timothy channels. These results identify the CaN-binding site as the long-sought VDI-regulatory motif of the cardiac channel. The substantial increase in VDI and the accelerated inactivation caused by the selective inhibitors of CaN, cyclosporine A and FK-506, which act at the same CaN-binding site, further support this conclusion. A reversal of enhanced-sympathetic tone by VDI-enhancing CaN inhibitors could be beneficial for improving Timothy syndrome complications such as long-QT and autism. |
format | Online Article Text |
id | pubmed-3328044 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-33280442012-04-17 Calcineurin Controls Voltage-Dependent-Inactivation (VDI) of the Normal and Timothy Cardiac Channels Cohen-Kutner, Moshe Yahalom, Yfat Trus, Michael Atlas, Daphne Sci Rep Article Ca(2+)-entry in the heart is tightly controlled by Cav1.2 inactivation, which involves Ca(2+)-dependent inactivation (CDI) and voltage-dependent inactivation (VDI) components. Timothy syndrome, a subtype-form of congenital long-QT syndrome, results from a nearly complete elimination of VDI by the G406R mutation in the α(1)1.2 subunit of Cav1.2. Here, we show that a single (A1929P) or a double mutation (H1926A-H1927A) within the CaN-binding site at the human C-terminal tail of α(1)1.2, accelerate the inactivation rate and enhances VDI of both wt and Timothy channels. These results identify the CaN-binding site as the long-sought VDI-regulatory motif of the cardiac channel. The substantial increase in VDI and the accelerated inactivation caused by the selective inhibitors of CaN, cyclosporine A and FK-506, which act at the same CaN-binding site, further support this conclusion. A reversal of enhanced-sympathetic tone by VDI-enhancing CaN inhibitors could be beneficial for improving Timothy syndrome complications such as long-QT and autism. Nature Publishing Group 2012-04-17 /pmc/articles/PMC3328044/ /pubmed/22511998 http://dx.doi.org/10.1038/srep00366 Text en Copyright © 2012, Macmillan Publishers Limited. All rights reserved http://creativecommons.org/licenses/by-nc-sa/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-ShareALike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/ |
spellingShingle | Article Cohen-Kutner, Moshe Yahalom, Yfat Trus, Michael Atlas, Daphne Calcineurin Controls Voltage-Dependent-Inactivation (VDI) of the Normal and Timothy Cardiac Channels |
title | Calcineurin Controls Voltage-Dependent-Inactivation (VDI) of the Normal and Timothy Cardiac Channels |
title_full | Calcineurin Controls Voltage-Dependent-Inactivation (VDI) of the Normal and Timothy Cardiac Channels |
title_fullStr | Calcineurin Controls Voltage-Dependent-Inactivation (VDI) of the Normal and Timothy Cardiac Channels |
title_full_unstemmed | Calcineurin Controls Voltage-Dependent-Inactivation (VDI) of the Normal and Timothy Cardiac Channels |
title_short | Calcineurin Controls Voltage-Dependent-Inactivation (VDI) of the Normal and Timothy Cardiac Channels |
title_sort | calcineurin controls voltage-dependent-inactivation (vdi) of the normal and timothy cardiac channels |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3328044/ https://www.ncbi.nlm.nih.gov/pubmed/22511998 http://dx.doi.org/10.1038/srep00366 |
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