Veale, Emma L., Hassan, Mustafa, Walsh, Yvonne, Al-Moubarak, Ehab, Mathie, Alistair (2014) Recovery of current through mutated TASK3 potassium channels underlying Birk Barel syndrome. Molecular pharmacology, 85 (3). pp. 397-407. ISSN 1521-0111. (doi:10.1124/mol.113.090530) (Access to this publication is currently restricted. You may be able to access a copy if URLs are provided) (KAR id:75884)
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Official URL: https://doi.org/10.1124/mol.113.090530 |
Abstract
TASK3 (TWIK-related acid-sensitive K(+) channel 3) potassium channels are members of the two-pore-domain potassium channel family. They are responsible for background leak potassium currents found in many cell types. TASK3 channels are genetically imprinted, and a mutation in TASK3 (G236R) is responsible for Birk Barel mental retardation dysmorphism syndrome, a maternally transmitted developmental disorder. This syndrome may arise from a neuronal migration defect during development caused by dysfunctional TASK3 channels. Through the use of whole-cell electrophysiologic recordings, we have found that, although G236R mutated TASK3 channels give rise to a functional current, this current is significantly smaller in an outward direction when compared with wild-type (WT) TASK3 channels. In contrast to WT TASK3 channels, the current is inwardly rectifying. Furthermore, the current through mutated channels is differentially sensitive to a number of regulators, such as extracellular acidification, extracellular zinc, and activation of Gαq-coupled muscarinic (M3) receptors, compared with WT TASK3 channels. The reduced outward current through mutated TASK3_G236R channels can be overcome, at least in part, by both a gain-of-function additional mutation of TASK3 channels (A237T) or by application of the nonsteroidal anti-inflammatory drug flufenamic acid (FFA; 2-{[3-(trifluoromethyl)phenyl]amino}benzoic acid). FFA produces a significantly greater enhancement of current through mutated channels than through WT TASK3 channels. We propose that pharmacologic enhancement of mutated TASK3 channel current during development may, therefore, provide a potentially useful therapeutic strategy in the treatment of Birk Barel syndrome.
Item Type: | Article |
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DOI/Identification number: | 10.1124/mol.113.090530 |
Subjects: | R Medicine |
Divisions: | Divisions > Division of Natural Sciences > Medway School of Pharmacy |
Depositing User: | Emma Veale |
Date Deposited: | 19 Aug 2019 21:52 UTC |
Last Modified: | 17 Aug 2022 11:02 UTC |
Resource URI: | https://kar.kent.ac.uk/id/eprint/75884 (The current URI for this page, for reference purposes) |
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