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The p.P888L SAP97 polymorphism increases the transient outward current (I(to,f)) and abbreviates the action potential duration and the QT interval
Synapse-Associated Protein 97 (SAP97) is an anchoring protein that in cardiomyocytes targets to the membrane and regulates Na(+) and K(+) channels. Here we compared the electrophysiological effects of native (WT) and p.P888L SAP97, a common polymorphism. Currents were recorded in cardiomyocytes from...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329876/ https://www.ncbi.nlm.nih.gov/pubmed/32612162 http://dx.doi.org/10.1038/s41598-020-67109-z |
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author | Tinaquero, David Crespo-García, Teresa Utrilla, Raquel G. Nieto-Marín, Paloma González-Guerra, Andrés Rubio-Alarcón, Marcos Cámara-Checa, Anabel Dago, María Matamoros, Marcos Pérez-Hernández, Marta Tamargo, María Cebrián, Jorge Jalife, José Tamargo, Juan Bernal, Juan Antonio Caballero, Ricardo Delpón, Eva |
author_facet | Tinaquero, David Crespo-García, Teresa Utrilla, Raquel G. Nieto-Marín, Paloma González-Guerra, Andrés Rubio-Alarcón, Marcos Cámara-Checa, Anabel Dago, María Matamoros, Marcos Pérez-Hernández, Marta Tamargo, María Cebrián, Jorge Jalife, José Tamargo, Juan Bernal, Juan Antonio Caballero, Ricardo Delpón, Eva |
author_sort | Tinaquero, David |
collection | PubMed |
description | Synapse-Associated Protein 97 (SAP97) is an anchoring protein that in cardiomyocytes targets to the membrane and regulates Na(+) and K(+) channels. Here we compared the electrophysiological effects of native (WT) and p.P888L SAP97, a common polymorphism. Currents were recorded in cardiomyocytes from mice trans-expressing human WT or p.P888L SAP97 and in Chinese hamster ovary (CHO)-transfected cells. The duration of the action potentials and the QT interval were significantly shorter in p.P888L-SAP97 than in WT-SAP97 mice. Compared to WT, p.P888L SAP97 significantly increased the charge of the Ca-independent transient outward (I(to,f)) current in cardiomyocytes and the charge crossing Kv4.3 channels in CHO cells by slowing Kv4.3 inactivation kinetics. Silencing or inhibiting Ca/calmodulin kinase II (CaMKII) abolished the p.P888L-induced Kv4.3 charge increase, which was also precluded in channels (p.S550A Kv4.3) in which the CaMKII-phosphorylation is prevented. Computational protein-protein docking predicted that p.P888L SAP97 is more likely to form a complex with CaMKII than WT. The Na(+) current and the current generated by Kv1.5 channels increased similarly in WT-SAP97 and p.P888L-SAP97 cardiomyocytes, while the inward rectifier current increased in WT-SAP97 but not in p.P888L-SAP97 cardiomyocytes. The p.P888L SAP97 polymorphism increases the I(to,f), a CaMKII-dependent effect that may increase the risk of arrhythmias. |
format | Online Article Text |
id | pubmed-7329876 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-73298762020-07-06 The p.P888L SAP97 polymorphism increases the transient outward current (I(to,f)) and abbreviates the action potential duration and the QT interval Tinaquero, David Crespo-García, Teresa Utrilla, Raquel G. Nieto-Marín, Paloma González-Guerra, Andrés Rubio-Alarcón, Marcos Cámara-Checa, Anabel Dago, María Matamoros, Marcos Pérez-Hernández, Marta Tamargo, María Cebrián, Jorge Jalife, José Tamargo, Juan Bernal, Juan Antonio Caballero, Ricardo Delpón, Eva Sci Rep Article Synapse-Associated Protein 97 (SAP97) is an anchoring protein that in cardiomyocytes targets to the membrane and regulates Na(+) and K(+) channels. Here we compared the electrophysiological effects of native (WT) and p.P888L SAP97, a common polymorphism. Currents were recorded in cardiomyocytes from mice trans-expressing human WT or p.P888L SAP97 and in Chinese hamster ovary (CHO)-transfected cells. The duration of the action potentials and the QT interval were significantly shorter in p.P888L-SAP97 than in WT-SAP97 mice. Compared to WT, p.P888L SAP97 significantly increased the charge of the Ca-independent transient outward (I(to,f)) current in cardiomyocytes and the charge crossing Kv4.3 channels in CHO cells by slowing Kv4.3 inactivation kinetics. Silencing or inhibiting Ca/calmodulin kinase II (CaMKII) abolished the p.P888L-induced Kv4.3 charge increase, which was also precluded in channels (p.S550A Kv4.3) in which the CaMKII-phosphorylation is prevented. Computational protein-protein docking predicted that p.P888L SAP97 is more likely to form a complex with CaMKII than WT. The Na(+) current and the current generated by Kv1.5 channels increased similarly in WT-SAP97 and p.P888L-SAP97 cardiomyocytes, while the inward rectifier current increased in WT-SAP97 but not in p.P888L-SAP97 cardiomyocytes. The p.P888L SAP97 polymorphism increases the I(to,f), a CaMKII-dependent effect that may increase the risk of arrhythmias. Nature Publishing Group UK 2020-07-01 /pmc/articles/PMC7329876/ /pubmed/32612162 http://dx.doi.org/10.1038/s41598-020-67109-z Text en © The Author(s) 2020 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Tinaquero, David Crespo-García, Teresa Utrilla, Raquel G. Nieto-Marín, Paloma González-Guerra, Andrés Rubio-Alarcón, Marcos Cámara-Checa, Anabel Dago, María Matamoros, Marcos Pérez-Hernández, Marta Tamargo, María Cebrián, Jorge Jalife, José Tamargo, Juan Bernal, Juan Antonio Caballero, Ricardo Delpón, Eva The p.P888L SAP97 polymorphism increases the transient outward current (I(to,f)) and abbreviates the action potential duration and the QT interval |
title | The p.P888L SAP97 polymorphism increases the transient outward current (I(to,f)) and abbreviates the action potential duration and the QT interval |
title_full | The p.P888L SAP97 polymorphism increases the transient outward current (I(to,f)) and abbreviates the action potential duration and the QT interval |
title_fullStr | The p.P888L SAP97 polymorphism increases the transient outward current (I(to,f)) and abbreviates the action potential duration and the QT interval |
title_full_unstemmed | The p.P888L SAP97 polymorphism increases the transient outward current (I(to,f)) and abbreviates the action potential duration and the QT interval |
title_short | The p.P888L SAP97 polymorphism increases the transient outward current (I(to,f)) and abbreviates the action potential duration and the QT interval |
title_sort | p.p888l sap97 polymorphism increases the transient outward current (i(to,f)) and abbreviates the action potential duration and the qt interval |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329876/ https://www.ncbi.nlm.nih.gov/pubmed/32612162 http://dx.doi.org/10.1038/s41598-020-67109-z |
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