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Drug-induced ion channel opening tuned by the voltage sensor charge profile
Polyunsaturated fatty acids modulate the voltage dependence of several voltage-gated ion channels, thereby being potent modifiers of cellular excitability. Detailed knowledge of this molecular mechanism can be used in designing a new class of small-molecule compounds against hyperexcitability diseas...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4001773/ https://www.ncbi.nlm.nih.gov/pubmed/24420769 http://dx.doi.org/10.1085/jgp.201311087 |
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author | Ottosson, Nina E. Liin, Sara I. Elinder, Fredrik |
author_facet | Ottosson, Nina E. Liin, Sara I. Elinder, Fredrik |
author_sort | Ottosson, Nina E. |
collection | PubMed |
description | Polyunsaturated fatty acids modulate the voltage dependence of several voltage-gated ion channels, thereby being potent modifiers of cellular excitability. Detailed knowledge of this molecular mechanism can be used in designing a new class of small-molecule compounds against hyperexcitability diseases. Here, we show that arginines on one side of the helical K-channel voltage sensor S4 increased the sensitivity to docosahexaenoic acid (DHA), whereas arginines on the opposing side decreased this sensitivity. Glutamates had opposite effects. In addition, a positively charged DHA-like molecule, arachidonyl amine, had opposite effects to the negatively charged DHA. This suggests that S4 rotates to open the channel and that DHA electrostatically affects this rotation. A channel with arginines in positions 356, 359, and 362 was extremely sensitive to DHA: 70 µM DHA at pH 9.0 increased the current >500 times at negative voltages compared with wild type (WT). The small-molecule compound pimaric acid, a novel Shaker channel opener, opened the WT channel. The 356R/359R/362R channel drastically increased this effect, suggesting it to be instrumental in future drug screening. |
format | Online Article Text |
id | pubmed-4001773 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-40017732014-08-01 Drug-induced ion channel opening tuned by the voltage sensor charge profile Ottosson, Nina E. Liin, Sara I. Elinder, Fredrik J Gen Physiol Research Articles Polyunsaturated fatty acids modulate the voltage dependence of several voltage-gated ion channels, thereby being potent modifiers of cellular excitability. Detailed knowledge of this molecular mechanism can be used in designing a new class of small-molecule compounds against hyperexcitability diseases. Here, we show that arginines on one side of the helical K-channel voltage sensor S4 increased the sensitivity to docosahexaenoic acid (DHA), whereas arginines on the opposing side decreased this sensitivity. Glutamates had opposite effects. In addition, a positively charged DHA-like molecule, arachidonyl amine, had opposite effects to the negatively charged DHA. This suggests that S4 rotates to open the channel and that DHA electrostatically affects this rotation. A channel with arginines in positions 356, 359, and 362 was extremely sensitive to DHA: 70 µM DHA at pH 9.0 increased the current >500 times at negative voltages compared with wild type (WT). The small-molecule compound pimaric acid, a novel Shaker channel opener, opened the WT channel. The 356R/359R/362R channel drastically increased this effect, suggesting it to be instrumental in future drug screening. The Rockefeller University Press 2014-02 /pmc/articles/PMC4001773/ /pubmed/24420769 http://dx.doi.org/10.1085/jgp.201311087 Text en © 2014 Ottosson et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Research Articles Ottosson, Nina E. Liin, Sara I. Elinder, Fredrik Drug-induced ion channel opening tuned by the voltage sensor charge profile |
title | Drug-induced ion channel opening tuned by the voltage sensor charge profile |
title_full | Drug-induced ion channel opening tuned by the voltage sensor charge profile |
title_fullStr | Drug-induced ion channel opening tuned by the voltage sensor charge profile |
title_full_unstemmed | Drug-induced ion channel opening tuned by the voltage sensor charge profile |
title_short | Drug-induced ion channel opening tuned by the voltage sensor charge profile |
title_sort | drug-induced ion channel opening tuned by the voltage sensor charge profile |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4001773/ https://www.ncbi.nlm.nih.gov/pubmed/24420769 http://dx.doi.org/10.1085/jgp.201311087 |
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