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Polymodal activation of the TREK-2 K2P channel produces structurally distinct open states
The TREK subfamily of two-pore domain (K2P) K(+) channels exhibit polymodal gating by a wide range of physical and chemical stimuli. Crystal structures now exist for these channels in two main states referred to as the “up” and “down” conformations. However, recent studies have resulted in contradic...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4886281/ https://www.ncbi.nlm.nih.gov/pubmed/27241700 http://dx.doi.org/10.1085/jgp.201611601 |
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author | McClenaghan, Conor Schewe, Marcus Aryal, Prafulla Carpenter, Elisabeth P. Baukrowitz, Thomas Tucker, Stephen J. |
author_facet | McClenaghan, Conor Schewe, Marcus Aryal, Prafulla Carpenter, Elisabeth P. Baukrowitz, Thomas Tucker, Stephen J. |
author_sort | McClenaghan, Conor |
collection | PubMed |
description | The TREK subfamily of two-pore domain (K2P) K(+) channels exhibit polymodal gating by a wide range of physical and chemical stimuli. Crystal structures now exist for these channels in two main states referred to as the “up” and “down” conformations. However, recent studies have resulted in contradictory and mutually exclusive conclusions about the functional (i.e., conductive) status of these two conformations. To address this problem, we have used the state-dependent TREK-2 inhibitor norfluoxetine that can only bind to the down state, thereby allowing us to distinguish between these two conformations when activated by different stimuli. Our results reconcile these previously contradictory gating models by demonstrating that activation by pressure, temperature, voltage, and pH produce more than one structurally distinct open state and reveal that channel activation does not simply involve switching between the up and down conformations. These results also highlight the diversity of structural mechanisms that K2P channels use to integrate polymodal gating signals. |
format | Online Article Text |
id | pubmed-4886281 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-48862812016-12-01 Polymodal activation of the TREK-2 K2P channel produces structurally distinct open states McClenaghan, Conor Schewe, Marcus Aryal, Prafulla Carpenter, Elisabeth P. Baukrowitz, Thomas Tucker, Stephen J. J Gen Physiol Research Articles The TREK subfamily of two-pore domain (K2P) K(+) channels exhibit polymodal gating by a wide range of physical and chemical stimuli. Crystal structures now exist for these channels in two main states referred to as the “up” and “down” conformations. However, recent studies have resulted in contradictory and mutually exclusive conclusions about the functional (i.e., conductive) status of these two conformations. To address this problem, we have used the state-dependent TREK-2 inhibitor norfluoxetine that can only bind to the down state, thereby allowing us to distinguish between these two conformations when activated by different stimuli. Our results reconcile these previously contradictory gating models by demonstrating that activation by pressure, temperature, voltage, and pH produce more than one structurally distinct open state and reveal that channel activation does not simply involve switching between the up and down conformations. These results also highlight the diversity of structural mechanisms that K2P channels use to integrate polymodal gating signals. The Rockefeller University Press 2016-06 /pmc/articles/PMC4886281/ /pubmed/27241700 http://dx.doi.org/10.1085/jgp.201611601 Text en © 2016 McClenaghan 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 McClenaghan, Conor Schewe, Marcus Aryal, Prafulla Carpenter, Elisabeth P. Baukrowitz, Thomas Tucker, Stephen J. Polymodal activation of the TREK-2 K2P channel produces structurally distinct open states |
title | Polymodal activation of the TREK-2 K2P channel produces structurally distinct open states |
title_full | Polymodal activation of the TREK-2 K2P channel produces structurally distinct open states |
title_fullStr | Polymodal activation of the TREK-2 K2P channel produces structurally distinct open states |
title_full_unstemmed | Polymodal activation of the TREK-2 K2P channel produces structurally distinct open states |
title_short | Polymodal activation of the TREK-2 K2P channel produces structurally distinct open states |
title_sort | polymodal activation of the trek-2 k2p channel produces structurally distinct open states |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4886281/ https://www.ncbi.nlm.nih.gov/pubmed/27241700 http://dx.doi.org/10.1085/jgp.201611601 |
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