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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American Society for Biochemistry and Molecular Biology Publications
2020
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| Online Access: | http://irep.iium.edu.my/79624/ 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 |
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| 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 |
| building | IIUM Repository |
| collection | Online Access |
| 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. |
| first_indexed | 2025-11-14T17:46:37Z |
| format | Article |
| id | iium-79624 |
| institution | International Islamic University Malaysia |
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| language | English English English English |
| last_indexed | 2025-11-14T17:46:37Z |
| publishDate | 2020 |
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| recordtype | eprints |
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| spelling | iium-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 |
| 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 |
| title | 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_short | 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 |
| topic | QC Physics QP Physiology TP248.13 Biotechnology |
| url | http://irep.iium.edu.my/79624/ http://irep.iium.edu.my/79624/ 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 |