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

• Published in: Biochemical and biophysical research communications 2017-11, Vol.493 (1), p.444-450
• Main Authors: Wright, Paul D., Veale, Emma L., McCoull, David, Tickle, David C., Large, Jonathan M., Ococks, Emma, Gothard, Gemma, Kettleborough, Catherine, Mathie, Alistair, Jerman, Jeffrey
• Format: Article
• Language: English
• Subjects: Activator; Drug Evaluation, Preclinical - methods; Ion Channel Gating - drug effects; Ion Channel Gating - physiology; K2P; KCNK9; Naphthalenes - administration & dosage; Naphthalenes - chemistry; Porosity; Potassium - chemistry; Potassium - metabolism; Potassium Channels, Tandem Pore Domain - agonists; Potassium Channels, Tandem Pore Domain - metabolism; Protein Domains; Structure-Activity Relationship; TASK3; Terbinafine
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2017.09.002

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. •Two-pore domain potassium channels (K2Ps) carry background (or leak) potassium current.•Lack of specific, pharmacological tools for K2Ps.•Developed a cell-based assay to identify activators of TASK3.•Terbinafine is a selective activator of TASK3.