Wright, Paul D., Veale, Emma L., McCoull, David, Tickle, David C., Large, Jonathan M., Ococks, Emma, Gothard, Gemma, Kettleborough, Catherine, Mathie, Alistair, Jerman, Jeffrey and others. (2017) Terbinafine is a novel and selective activator of the two-pore domain potassium channel TASK3. Biochemical and Biophysical Research Communications, 493 (1). pp. 444-450. ISSN 0006-291X. E-ISSN 1090-2104. (doi:10.1016/j.bbrc.2017.09.002) (KAR id:63377)
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Official URL: http://dx.doi.org/10.1016/j.bbrc.2017.09.002 |
Abstract
Two-pore domain potassium channels (K2Ps) are characterized by their four transmembrane domain and two-pore topology. They carry background (or leak) potassium current in a variety of cell types. Despite a number of important roles there is currently a lack of pharmacological tools with which to further probe K2P function. We have developed a cell-based thallium flux assay, using baculovirus delivered TASK3 (TWIK-related acid-sensitive K+ channel 3, KCNK9, K2P9.1) with the aim of identifying novel, selective TASK3 activators. After screening a library of 1000 compounds, including drug-like and FDA approved molecules, we identified Terbinafine as an activator of TASK3. In a thallium flux assay a pEC50 of 6.2 ( ±0.12) was observed. When Terbinafine was screened against TASK2, TREK2, THIK1, TWIK1 and TRESK no activation was observed in thallium flux assays. Several analogues of Terbinafine were also purchased and structure activity relationships examined. To confirm Terbinafine's activation of TASK3 whole cell patch clamp electrophysiology was carried out and clear potentiation observed in both the wild type channel and the pathophysiological, Birk-Barel syndrome associated, G236R TASK3 mutant. No activity at TASK1 was observed in electrophysiology studies. In conclusion, we have identified the first selective activator of the two-pore domain potassium channel TASK3.
Item Type: | Article |
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DOI/Identification number: | 10.1016/j.bbrc.2017.09.002 |
Uncontrolled keywords: | TASK3; Activator; K2P; KCNK9; Terbinafine |
Subjects: | Q Science |
Divisions: | Divisions > Division of Natural Sciences > Medway School of Pharmacy |
Depositing User: | Alistair Mathie |
Date Deposited: | 12 Sep 2017 13:12 UTC |
Last Modified: | 09 Jan 2024 22:22 UTC |
Resource URI: | https://kar.kent.ac.uk/id/eprint/63377 (The current URI for this page, for reference purposes) |
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