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Multiple Modulation of Acid-Sensing Ion Channel 1a by the Alkaloid Daurisoline
Acid-sensing ion channels (ASICs) are proton-gated sodium-selective channels that are expressed in the peripheral and central nervous systems. ASIC1a is one of the most intensively studied isoforms due to its importance and wide representation in organisms, but it is still largely unexplored as a ta...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722837/ https://www.ncbi.nlm.nih.gov/pubmed/31382492 http://dx.doi.org/10.3390/biom9080336 |
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author | Osmakov, Dmitry I. Koshelev, Sergey G. Lyukmanova, Ekaterina N. Shulepko, Mikhail A. Andreev, Yaroslav A. Illes, Peter Kozlov, Sergey A. |
author_facet | Osmakov, Dmitry I. Koshelev, Sergey G. Lyukmanova, Ekaterina N. Shulepko, Mikhail A. Andreev, Yaroslav A. Illes, Peter Kozlov, Sergey A. |
author_sort | Osmakov, Dmitry I. |
collection | PubMed |
description | Acid-sensing ion channels (ASICs) are proton-gated sodium-selective channels that are expressed in the peripheral and central nervous systems. ASIC1a is one of the most intensively studied isoforms due to its importance and wide representation in organisms, but it is still largely unexplored as a target for therapy. In this study, we demonstrated response of the ASIC1a to acidification in the presence of the daurisoline (DAU) ligand. DAU alone did not activate the channel, but in combination with protons, it produced the second peak component of the ASIC1a current. This second peak differs from the sustained component (which is induced by RF-amide peptides), as the second (DAU-induced) peak is completely desensitized, with the same kinetics as the main peak. The co-application of DAU and mambalgin-2 indicated that their binding sites do not overlap. Additionally, we found an asymmetry in the pH activation curve of the channel, which was well-described by a mathematical model based on the multiplied probabilities of protons binding with a pool of high-cooperative sites and a single proton binding with a non-cooperative site. In this model, DAU targeted the pool of high-cooperative sites and, when applied with protons, acted as an inhibitor of ASIC1a activation. Moreover, DAU’s occupation of the same binding site most probably reverses the channel from steady-state desensitization in the pH 6.9–7.3 range. DAU features disclose new opportunities in studies of ASIC structure and function. |
format | Online Article Text |
id | pubmed-6722837 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-67228372019-09-10 Multiple Modulation of Acid-Sensing Ion Channel 1a by the Alkaloid Daurisoline Osmakov, Dmitry I. Koshelev, Sergey G. Lyukmanova, Ekaterina N. Shulepko, Mikhail A. Andreev, Yaroslav A. Illes, Peter Kozlov, Sergey A. Biomolecules Article Acid-sensing ion channels (ASICs) are proton-gated sodium-selective channels that are expressed in the peripheral and central nervous systems. ASIC1a is one of the most intensively studied isoforms due to its importance and wide representation in organisms, but it is still largely unexplored as a target for therapy. In this study, we demonstrated response of the ASIC1a to acidification in the presence of the daurisoline (DAU) ligand. DAU alone did not activate the channel, but in combination with protons, it produced the second peak component of the ASIC1a current. This second peak differs from the sustained component (which is induced by RF-amide peptides), as the second (DAU-induced) peak is completely desensitized, with the same kinetics as the main peak. The co-application of DAU and mambalgin-2 indicated that their binding sites do not overlap. Additionally, we found an asymmetry in the pH activation curve of the channel, which was well-described by a mathematical model based on the multiplied probabilities of protons binding with a pool of high-cooperative sites and a single proton binding with a non-cooperative site. In this model, DAU targeted the pool of high-cooperative sites and, when applied with protons, acted as an inhibitor of ASIC1a activation. Moreover, DAU’s occupation of the same binding site most probably reverses the channel from steady-state desensitization in the pH 6.9–7.3 range. DAU features disclose new opportunities in studies of ASIC structure and function. MDPI 2019-08-02 /pmc/articles/PMC6722837/ /pubmed/31382492 http://dx.doi.org/10.3390/biom9080336 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Osmakov, Dmitry I. Koshelev, Sergey G. Lyukmanova, Ekaterina N. Shulepko, Mikhail A. Andreev, Yaroslav A. Illes, Peter Kozlov, Sergey A. Multiple Modulation of Acid-Sensing Ion Channel 1a by the Alkaloid Daurisoline |
title | Multiple Modulation of Acid-Sensing Ion Channel 1a by the Alkaloid Daurisoline |
title_full | Multiple Modulation of Acid-Sensing Ion Channel 1a by the Alkaloid Daurisoline |
title_fullStr | Multiple Modulation of Acid-Sensing Ion Channel 1a by the Alkaloid Daurisoline |
title_full_unstemmed | Multiple Modulation of Acid-Sensing Ion Channel 1a by the Alkaloid Daurisoline |
title_short | Multiple Modulation of Acid-Sensing Ion Channel 1a by the Alkaloid Daurisoline |
title_sort | multiple modulation of acid-sensing ion channel 1a by the alkaloid daurisoline |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722837/ https://www.ncbi.nlm.nih.gov/pubmed/31382492 http://dx.doi.org/10.3390/biom9080336 |
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