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Influence of the N terminus on the biophysical properties and pharmacology of TREK1 potassium channels.

Veale, Emma L., Al-Moubarak, Ehab, Bajaria, Naina, Omoto, Kiyoyuki, Cao, Lishuang, Tucker, Stephen J, Stevens, Edward B, Mathie, Alistair (2014) Influence of the N terminus on the biophysical properties and pharmacology of TREK1 potassium channels. Molecular pharmacology, 85 (5). pp. 671-81. ISSN 1521-0111. (doi:10.1124/mol.113.091199) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided)

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Official URL
http://dx.doi.org/10.1124/mol.113.091199

Abstract

TWIK-related K(+) 1 (TREK1) potassium channels are members of the two-pore domain potassium channel family and contribute to background potassium conductances in many cell types, where their activity can be regulated by a variety of physiologic and pharmacologic mediators. Fenamates such as FFA (flufenamic acid; 2-{[3-(trifluoromethyl)phenyl]amino}benzoic acid), MFA [mefenamic acid; 2-(2,3-dimethylphenyl)aminobenzoic acid], NFA [niflumic acid; 2-{[3-(trifluoromethyl)phenyl]amino}nicotinic acid], and diclofenac [2-(2-(2,6-dichlorophenylamino)phenyl)acetic acid] and the related experimental drug BL-1249 [(5,6,7,8-tetrahydro-naphthalen-1-yl)-[2-(1H-tetrazol-5-yl)-phenyl]-amine] enhance the activity of TREK1 currents, and we show that BL-1249 is the most potent of these compounds. Alternative translation initiation produces a shorter, N terminus truncated form of TREK1 with a much reduced open probability and a proposed increased permeability to sodium compared with the longer form. We show that both forms of TREK1 can be activated by fenamates and that a number of mutations that affect TREK1 channel gating occlude the action of fenamates but only in the longer form of TREK1. Furthermore, fenamates produce a marked enhancement of current through the shorter, truncated form of TREK1 and reveal a K(+)-selective channel, like the long form. These results provide insight into the mechanism of TREK1 channel activation by fenamates, and, given the role of TREK1 channels in pain, they suggest a novel analgesic mechanism for these compounds.

Item Type: Article
DOI/Identification number: 10.1124/mol.113.091199
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculties > Sciences > Medway School of Pharmacy
Depositing User: Emma Veale
Date Deposited: 04 Dec 2015 13:29 UTC
Last Modified: 29 May 2019 16:36 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/52693 (The current URI for this page, for reference purposes)
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