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

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

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Abstract

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.

Item Type: Article (Journal)
Additional Information: 5236/79624
Uncontrolled Keywords: ion channel; potassium channel; gating; membrane biophysics; membrane protein
Subjects: Q Science > QC Physics
Q Science > QP Physiology
T Technology > TP Chemical technology > TP248.13 Biotechnology
Kulliyyahs/Centres/Divisions/Institutes (Can select more than one option. Press CONTROL button): Kulliyyah of Engineering > Department of Biotechnology Engineering
Kulliyyah of Engineering
Depositing User: Mohd Firdaus Abd Wahab
Date Deposited: 24 Apr 2020 11:25
Last Modified: 24 Apr 2020 11:25
URI: http://irep.iium.edu.my/id/eprint/79624

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