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Activation of SGK1.1 Upregulates the M-current in the Presence of Epilepsy Mutations
In the central nervous system, the M-current plays a critical role in regulating subthreshold electrical excitability of neurons, determining their firing properties and responsiveness to synaptic input. The M-channel is mainly formed by subunits Kv7.2 and Kv7.3 that co-assemble to form a heterotetr...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8662703/ https://www.ncbi.nlm.nih.gov/pubmed/34899186 http://dx.doi.org/10.3389/fnmol.2021.798261 |
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author | Martin-Batista, Elva Manville, Rían W. Rivero-Pérez, Belinda Bartolomé-Martín, David Alvarez de la Rosa, Diego Abbott, Geoffrey W. Giraldez, Teresa |
author_facet | Martin-Batista, Elva Manville, Rían W. Rivero-Pérez, Belinda Bartolomé-Martín, David Alvarez de la Rosa, Diego Abbott, Geoffrey W. Giraldez, Teresa |
author_sort | Martin-Batista, Elva |
collection | PubMed |
description | In the central nervous system, the M-current plays a critical role in regulating subthreshold electrical excitability of neurons, determining their firing properties and responsiveness to synaptic input. The M-channel is mainly formed by subunits Kv7.2 and Kv7.3 that co-assemble to form a heterotetrametric channel. Mutations in Kv7.2 and Kv7.3 are associated with hyperexcitability phenotypes including benign familial neonatal epilepsy (BFNE) and neonatal epileptic encephalopathy (NEE). SGK1.1, the neuronal isoform of the serum and glucocorticoids-regulated kinase 1 (SGK1), increases M-current density in neurons, leading to reduced excitability and protection against seizures. Herein, using two-electrode voltage clamp on Xenopus laevis oocytes, we demonstrate that SGK1.1 selectively activates heteromeric Kv7 subunit combinations underlying the M-current. Importantly, activated SGK1.1 increases M-channel activity in the presence of two different epilepsy mutations found in Kv7.2, R207W and A306T. In addition, proximity ligation assays in the N2a cell line allowed us to address the effect of these mutations on Kv7-SGK1.1-Nedd4 molecular associations, a proposed pathway underlying augmentation of M-channel activity by SGK1.1 |
format | Online Article Text |
id | pubmed-8662703 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-86627032021-12-11 Activation of SGK1.1 Upregulates the M-current in the Presence of Epilepsy Mutations Martin-Batista, Elva Manville, Rían W. Rivero-Pérez, Belinda Bartolomé-Martín, David Alvarez de la Rosa, Diego Abbott, Geoffrey W. Giraldez, Teresa Front Mol Neurosci Molecular Neuroscience In the central nervous system, the M-current plays a critical role in regulating subthreshold electrical excitability of neurons, determining their firing properties and responsiveness to synaptic input. The M-channel is mainly formed by subunits Kv7.2 and Kv7.3 that co-assemble to form a heterotetrametric channel. Mutations in Kv7.2 and Kv7.3 are associated with hyperexcitability phenotypes including benign familial neonatal epilepsy (BFNE) and neonatal epileptic encephalopathy (NEE). SGK1.1, the neuronal isoform of the serum and glucocorticoids-regulated kinase 1 (SGK1), increases M-current density in neurons, leading to reduced excitability and protection against seizures. Herein, using two-electrode voltage clamp on Xenopus laevis oocytes, we demonstrate that SGK1.1 selectively activates heteromeric Kv7 subunit combinations underlying the M-current. Importantly, activated SGK1.1 increases M-channel activity in the presence of two different epilepsy mutations found in Kv7.2, R207W and A306T. In addition, proximity ligation assays in the N2a cell line allowed us to address the effect of these mutations on Kv7-SGK1.1-Nedd4 molecular associations, a proposed pathway underlying augmentation of M-channel activity by SGK1.1 Frontiers Media S.A. 2021-11-26 /pmc/articles/PMC8662703/ /pubmed/34899186 http://dx.doi.org/10.3389/fnmol.2021.798261 Text en Copyright © 2021 Martin-Batista, Manville, Rivero-Pérez, Bartolomé-Martín, Alvarez de la Rosa, Abbott and Giraldez. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Molecular Neuroscience Martin-Batista, Elva Manville, Rían W. Rivero-Pérez, Belinda Bartolomé-Martín, David Alvarez de la Rosa, Diego Abbott, Geoffrey W. Giraldez, Teresa Activation of SGK1.1 Upregulates the M-current in the Presence of Epilepsy Mutations |
title | Activation of SGK1.1 Upregulates the M-current in the Presence of Epilepsy Mutations |
title_full | Activation of SGK1.1 Upregulates the M-current in the Presence of Epilepsy Mutations |
title_fullStr | Activation of SGK1.1 Upregulates the M-current in the Presence of Epilepsy Mutations |
title_full_unstemmed | Activation of SGK1.1 Upregulates the M-current in the Presence of Epilepsy Mutations |
title_short | Activation of SGK1.1 Upregulates the M-current in the Presence of Epilepsy Mutations |
title_sort | activation of sgk1.1 upregulates the m-current in the presence of epilepsy mutations |
topic | Molecular Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8662703/ https://www.ncbi.nlm.nih.gov/pubmed/34899186 http://dx.doi.org/10.3389/fnmol.2021.798261 |
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