Veale, Emma L., Hassan, Mustafa, Walsh, Yvonne, Al-Moubarak, Ehab and Mathie, Alistair (2014) 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 / School / Research Centre / Research Group:	Faculty of Engineering & Science Faculty of Engineering & Science > Medway School of Pharmacy
Last Modified:	19 Sep 2019 14:20
URI:	http://gala.gre.ac.uk/id/eprint/12195

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