Staff View: Selectivity filter instability dominates the low intrinsic activity of the TWIK-1 K2P K+ channel

Selectivity filter instability dominates the low intrinsic activity of the TWIK-1 K2P K+ channel

Two-pore domain K+ (K2P) channels have many important physiological functions. However, the functional properties of the TWIK-1 (K2P1.1/KCNK1) K2P channel remain poorly characterized because heterologous expression of this ion channel yields only very low levels of functional activity. Several under...

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Main Authors:	Nematian-Ardestani, Ehsan, Abd. Wahab, Mohd. Firdaus, Chatelain, Franck C., Sun, Han, Schewe, Marcus, Baukrowitz, Thomas, Tucker, Stephen J.
Format:	Article
Language:	English English English English
Published:	American Society for Biochemistry and Molecular Biology Publications 2020
Subjects:	QC Physics QP Physiology TP248.13 Biotechnology
Online Access:	http://irep.iium.edu.my/79624/1/79624_Selectivity%20filter%20instability%20dominates%20-%20pre-print.pdf http://irep.iium.edu.my/79624/2/79624_Selectivity%20filter%20instability%20dominates_MYRA.pdf http://irep.iium.edu.my/79624/3/79624_Selectivity%20filter%20instability%20dominates_SCOPUS.pdf http://irep.iium.edu.my/79624/4/79624_Selectivity%20filter%20instability%20dominates_WOS.pdf http://irep.iium.edu.my/79624/ https://www.jbc.org/content/295/2/610.short
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spelling	my.iium.irep.796242021-04-05T04:51:13Z http://irep.iium.edu.my/79624/ Selectivity filter instability dominates the low intrinsic activity of the TWIK-1 K2P K+ channel Nematian-Ardestani, Ehsan Abd. Wahab, Mohd. Firdaus Chatelain, Franck C. Sun, Han Schewe, Marcus Baukrowitz, Thomas Tucker, Stephen J. QC Physics QP Physiology TP248.13 Biotechnology Two-pore domain K+ (K2P) channels have many important physiological functions. However, the functional properties of the TWIK-1 (K2P1.1/KCNK1) K2P channel remain poorly characterized because heterologous expression of this ion channel yields only very low levels of functional activity. Several underlying reasons have been proposed, including TWIK-1 retention in intracellular organelles, inhibition by posttranslational sumoylation, a hydrophobic barrier within the pore, and a low open probability of the selectivity filter (SF) gate. By evaluating these potential mechanisms, we found that the latter dominates the low intrinsic functional activity of TWIK-1. Investigating this further, we observed that the low activity of the SF gate appears to arise from the inefficiency of K+ in stabilizing an active (i.e. conductive) SF conformation. In contrast, other permeant ion species, such as Rb+, NH4+, and Cs+, strongly promoted a pH-dependent activated conformation. Furthermore, many K2P channels are activated by membrane depolarization via an SF-mediated gating mechanism, but we found here that only very strong nonphysiological depolarization produces voltage-dependent activation of heterologously expressed TWIK-1. Remarkably, we also observed that TWIK-1 Rb+ currents are potently inhibited by intracellular K+ (IC50 = 2.8 mM). We conclude that TWIK-1 displays unique SF gating properties among the family of K2P channels. In particular, the apparent instability of the conductive conformation of the TWIK-1 SF in the presence of K+ appears to dominate the low levels of intrinsic functional activity observed when the channel is expressed at the cell surface. American Society for Biochemistry and Molecular Biology Publications 2020-01-10 Article PeerReviewed application/pdf en http://irep.iium.edu.my/79624/1/79624_Selectivity%20filter%20instability%20dominates%20-%20pre-print.pdf application/pdf en http://irep.iium.edu.my/79624/2/79624_Selectivity%20filter%20instability%20dominates_MYRA.pdf application/pdf en http://irep.iium.edu.my/79624/3/79624_Selectivity%20filter%20instability%20dominates_SCOPUS.pdf application/pdf en http://irep.iium.edu.my/79624/4/79624_Selectivity%20filter%20instability%20dominates_WOS.pdf Nematian-Ardestani, Ehsan and Abd. Wahab, Mohd. Firdaus and Chatelain, Franck C. and Sun, Han and Schewe, Marcus and Baukrowitz, Thomas and Tucker, Stephen J. (2020) Selectivity filter instability dominates the low intrinsic activity of the TWIK-1 K2P K+ channel. Journal of Biological Chemistry, 295 (2). pp. 610-618. ISSN 0021-9258 E-ISSN 1083-351X https://www.jbc.org/content/295/2/610.short
institution	Universiti Islam Antarabangsa Malaysia
building	IIUM Library
collection	Institutional Repository
continent	Asia
country	Malaysia
content_provider	International Islamic University Malaysia
content_source	IIUM Repository (IREP)
url_provider	http://irep.iium.edu.my/
language	English English English English
topic	QC Physics QP Physiology TP248.13 Biotechnology
spellingShingle	QC Physics QP Physiology TP248.13 Biotechnology Nematian-Ardestani, Ehsan Abd. Wahab, Mohd. Firdaus Chatelain, Franck C. Sun, Han Schewe, Marcus Baukrowitz, Thomas Tucker, Stephen J. Selectivity filter instability dominates the low intrinsic activity of the TWIK-1 K2P K+ channel
description	Two-pore domain K+ (K2P) channels have many important physiological functions. However, the functional properties of the TWIK-1 (K2P1.1/KCNK1) K2P channel remain poorly characterized because heterologous expression of this ion channel yields only very low levels of functional activity. Several underlying reasons have been proposed, including TWIK-1 retention in intracellular organelles, inhibition by posttranslational sumoylation, a hydrophobic barrier within the pore, and a low open probability of the selectivity filter (SF) gate. By evaluating these potential mechanisms, we found that the latter dominates the low intrinsic functional activity of TWIK-1. Investigating this further, we observed that the low activity of the SF gate appears to arise from the inefficiency of K+ in stabilizing an active (i.e. conductive) SF conformation. In contrast, other permeant ion species, such as Rb+, NH4+, and Cs+, strongly promoted a pH-dependent activated conformation. Furthermore, many K2P channels are activated by membrane depolarization via an SF-mediated gating mechanism, but we found here that only very strong nonphysiological depolarization produces voltage-dependent activation of heterologously expressed TWIK-1. Remarkably, we also observed that TWIK-1 Rb+ currents are potently inhibited by intracellular K+ (IC50 = 2.8 mM). We conclude that TWIK-1 displays unique SF gating properties among the family of K2P channels. In particular, the apparent instability of the conductive conformation of the TWIK-1 SF in the presence of K+ appears to dominate the low levels of intrinsic functional activity observed when the channel is expressed at the cell surface.
format	Article
author	Nematian-Ardestani, Ehsan Abd. Wahab, Mohd. Firdaus Chatelain, Franck C. Sun, Han Schewe, Marcus Baukrowitz, Thomas Tucker, Stephen J.
author_facet	Nematian-Ardestani, Ehsan Abd. Wahab, Mohd. Firdaus Chatelain, Franck C. Sun, Han Schewe, Marcus Baukrowitz, Thomas Tucker, Stephen J.
author_sort	Nematian-Ardestani, Ehsan
title	Selectivity filter instability dominates the low intrinsic activity of the TWIK-1 K2P K+ channel
title_short	Selectivity filter instability dominates the low intrinsic activity of the TWIK-1 K2P K+ channel
title_full	Selectivity filter instability dominates the low intrinsic activity of the TWIK-1 K2P K+ channel
title_fullStr	Selectivity filter instability dominates the low intrinsic activity of the TWIK-1 K2P K+ channel
title_full_unstemmed	Selectivity filter instability dominates the low intrinsic activity of the TWIK-1 K2P K+ channel
title_sort	selectivity filter instability dominates the low intrinsic activity of the twik-1 k2p k+ channel
publisher	American Society for Biochemistry and Molecular Biology Publications
publishDate	2020
url	http://irep.iium.edu.my/79624/1/79624_Selectivity%20filter%20instability%20dominates%20-%20pre-print.pdf http://irep.iium.edu.my/79624/2/79624_Selectivity%20filter%20instability%20dominates_MYRA.pdf http://irep.iium.edu.my/79624/3/79624_Selectivity%20filter%20instability%20dominates_SCOPUS.pdf http://irep.iium.edu.my/79624/4/79624_Selectivity%20filter%20instability%20dominates_WOS.pdf http://irep.iium.edu.my/79624/ https://www.jbc.org/content/295/2/610.short
_version_	1696976063241912320
score	13.211869

Selectivity filter instability dominates the low intrinsic activity of the TWIK-1 K2P K+ channel

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