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Recovery of current through mutated TASK3 potassium channels underlying Birk Barel syndrome

Recovery of current through mutated TASK3 potassium channels underlying Birk Barel syndrome

Veale, Emma L., Hassan, Mustafa, Walsh, Yvonne, Al-Moubarak, Ehab and Mathie, Alistair (2013) Recovery of current through mutated TASK3 potassium channels underlying Birk Barel syndrome. Molecular Pharmacology, 85 (3). pp. 397-407. ISSN 0026-895X (Print), 1521-0111 (Online) (doi:https://doi.org/10.1124/mol.113.090530)

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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
Additional Information: [1] This work was supported by the Biotechnology and Biological Sciences Research Council [Grant BB/J000930/1]. A.M. is a Royal Society Industry Fellow [Grant IF080012/AM].
Uncontrolled Keywords: TASK3, (TWIK-related acid-sensitive K+ channel 3), cell line, craniofacial abnormalities, HEK293 cells, intellectual disability, membrane potentials, muscle hypotonia, mutation, potassium channels, tandem pore domain, receptor, muscarinic M3, zinc
Subjects: R Medicine > RS Pharmacy and materia medica
Faculty / Department / Research Group: Faculty of Engineering & Science
Faculty of Engineering & Science > Medway School of Pharmacy
Related URLs:
Last Modified: 07 Jul 2016 13:57
Selected for GREAT 2016: None
Selected for GREAT 2017: None
Selected for GREAT 2018: None
Selected for GREAT 2019: None
URI: http://gala.gre.ac.uk/id/eprint/12195

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