Skip to main content
Kent Academic Repository

Terbinafine is a novel and selective activator of the two-pore domain potassium channel TASK3

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)

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
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)

University of Kent Author Information

  • Depositors only (login required):

Total unique views for this document in KAR since July 2020. For more details click on the image.