Academic Journal
Terbinafine is a novel and selective activator of the two-pore domain potassium channel TASK3.
| Τίτλος: | Terbinafine is a novel and selective activator of the two-pore domain potassium channel TASK3. |
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| Συγγραφείς: | Wright PD; LifeArc, Accelerator Building, Open Innovation Campus, Stevenage, SG1 2FX, UK. Electronic address: Paul.wright@lifearc.org., Veale EL; Medway School of Pharmacy, University of Kent, Anson Building, Central Avenue, Chatham Maritime, Kent, ME4 4TB, UK., McCoull D; LifeArc, Accelerator Building, Open Innovation Campus, Stevenage, SG1 2FX, UK., Tickle DC; LifeArc, Accelerator Building, Open Innovation Campus, Stevenage, SG1 2FX, UK., Large JM; LifeArc, Accelerator Building, Open Innovation Campus, Stevenage, SG1 2FX, UK., Ococks E; LifeArc, Accelerator Building, Open Innovation Campus, Stevenage, SG1 2FX, UK., Gothard G; LifeArc, Accelerator Building, Open Innovation Campus, Stevenage, SG1 2FX, UK., Kettleborough C; LifeArc, Accelerator Building, Open Innovation Campus, Stevenage, SG1 2FX, UK., Mathie A; Medway School of Pharmacy, University of Kent, Anson Building, Central Avenue, Chatham Maritime, Kent, ME4 4TB, UK., Jerman J; LifeArc, Accelerator Building, Open Innovation Campus, Stevenage, SG1 2FX, UK. |
| Πηγή: | Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2017 Nov 04; Vol. 493 (1), pp. 444-450. Date of Electronic Publication: 2017 Sep 05. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Country of Publication: United States NLM ID: 0372516 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2104 (Electronic) Linking ISSN: 0006291X NLM ISO Abbreviation: Biochem Biophys Res Commun Subsets: MEDLINE |
| Imprint Name(s): | Publication: <2002- >: San Diego, CA : Elsevier Original Publication: New York, Academic Press. |
| Ιατρικοί όροι (MeSH): | Drug Evaluation, Preclinical/*methods , Ion Channel Gating/*physiology , Naphthalenes/*administration & dosage , Naphthalenes/*chemistry , Potassium/*metabolism , Potassium Channels, Tandem Pore Domain/*agonists , Potassium Channels, Tandem Pore Domain/*metabolism, Ion Channel Gating/drug effects ; Potassium/chemistry ; Porosity ; Protein Domains ; Structure-Activity Relationship ; Terbinafine |
| Περίληψη: | 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. (Copyright © 2017 Elsevier Inc. All rights reserved.) |
| Contributed Indexing: | Keywords: Activator; K2P; KCNK9; TASK3; Terbinafine |
| Substance Nomenclature: | 0 (KCNK9 protein, human) 0 (Naphthalenes) 0 (Potassium Channels, Tandem Pore Domain) G7RIW8S0XP (Terbinafine) RWP5GA015D (Potassium) |
| Entry Date(s): | Date Created: 20170909 Date Completed: 20171023 Latest Revision: 20181202 |
| Update Code: | 20260130 |
| DOI: | 10.1016/j.bbrc.2017.09.002 |
| PMID: | 28882594 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1090-2104 |
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| DOI: | 10.1016/j.bbrc.2017.09.002 |