Effects of ionic strength on gating and permeation of TREK-2 K2P channels.

In addition to the classical voltage-dependent behavior mediated by the voltage-sensing-domains (VSD) of ion channels, a growing number of voltage-dependent gating behaviors are being described in channels that lack canonical VSDs. A common thread in their mechanism of action is the contribution of...

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Autores principales:	Linus J Conrad, Peter Proks, Stephen J Tucker
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e00ec64f68284455b9dbe1737546126d
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spelling	oai:doaj.org-article:e00ec64f68284455b9dbe1737546126d2021-12-02T20:13:46ZEffects of ionic strength on gating and permeation of TREK-2 K2P channels.1932-620310.1371/journal.pone.0258275https://doaj.org/article/e00ec64f68284455b9dbe1737546126d2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0258275https://doaj.org/toc/1932-6203In addition to the classical voltage-dependent behavior mediated by the voltage-sensing-domains (VSD) of ion channels, a growing number of voltage-dependent gating behaviors are being described in channels that lack canonical VSDs. A common thread in their mechanism of action is the contribution of the permeating ion to this voltage sensing process. The polymodal K2P K+ channel, TREK2 responds to membrane voltage through a gating process mediated by the interaction of K+ with its selectivity filter. Recently, we found that this action can be modulated by small molecule agonists (e.g. BL1249) which appear to have an electrostatic influence on K+ binding within the inner cavity and produce an increase in the single-channel conductance of TREK-2 channels. Here, we directly probed this K+-dependent gating process by recording both macroscopic and single-channel currents of TREK-2 in the presence of high concentrations of internal K+. Surprisingly we found TREK-2 is inhibited by high internal K+ concentrations and that this is mediated by the concomitant increase in ionic-strength. However, we were still able to determine that the increase in single channel conductance in the presence of BL1249 was blunted in high ionic-strength, whilst its activatory effect (on channel open probability) persisted. These effects are consistent with an electrostatic mechanism of action of negatively charged activators such as BL1249 on permeation, but also suggest that their influence on channel gating is complex.Linus J ConradPeter ProksStephen J TuckerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 10, p e0258275 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Linus J Conrad Peter Proks Stephen J Tucker Effects of ionic strength on gating and permeation of TREK-2 K2P channels.
description	In addition to the classical voltage-dependent behavior mediated by the voltage-sensing-domains (VSD) of ion channels, a growing number of voltage-dependent gating behaviors are being described in channels that lack canonical VSDs. A common thread in their mechanism of action is the contribution of the permeating ion to this voltage sensing process. The polymodal K2P K+ channel, TREK2 responds to membrane voltage through a gating process mediated by the interaction of K+ with its selectivity filter. Recently, we found that this action can be modulated by small molecule agonists (e.g. BL1249) which appear to have an electrostatic influence on K+ binding within the inner cavity and produce an increase in the single-channel conductance of TREK-2 channels. Here, we directly probed this K+-dependent gating process by recording both macroscopic and single-channel currents of TREK-2 in the presence of high concentrations of internal K+. Surprisingly we found TREK-2 is inhibited by high internal K+ concentrations and that this is mediated by the concomitant increase in ionic-strength. However, we were still able to determine that the increase in single channel conductance in the presence of BL1249 was blunted in high ionic-strength, whilst its activatory effect (on channel open probability) persisted. These effects are consistent with an electrostatic mechanism of action of negatively charged activators such as BL1249 on permeation, but also suggest that their influence on channel gating is complex.
format	article
author	Linus J Conrad Peter Proks Stephen J Tucker
author_facet	Linus J Conrad Peter Proks Stephen J Tucker
author_sort	Linus J Conrad
title	Effects of ionic strength on gating and permeation of TREK-2 K2P channels.
title_short	Effects of ionic strength on gating and permeation of TREK-2 K2P channels.
title_full	Effects of ionic strength on gating and permeation of TREK-2 K2P channels.
title_fullStr	Effects of ionic strength on gating and permeation of TREK-2 K2P channels.
title_full_unstemmed	Effects of ionic strength on gating and permeation of TREK-2 K2P channels.
title_sort	effects of ionic strength on gating and permeation of trek-2 k2p channels.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/e00ec64f68284455b9dbe1737546126d
work_keys_str_mv	AT linusjconrad effectsofionicstrengthongatingandpermeationoftrek2k2pchannels AT peterproks effectsofionicstrengthongatingandpermeationoftrek2k2pchannels AT stephenjtucker effectsofionicstrengthongatingandpermeationoftrek2k2pchannels
_version_	1718374737020715008

Effects of ionic strength on gating and permeation of TREK-2 K2P channels.

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