title: Recovery of current through mutated TASK3 potassium channels underlying Birk Barel syndrome.
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.
authors.affiliation: Medway School of Pharmacy, University of Kent and University of Greenwich, Kent, United Kingdom.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Veale
authors.forename: Mustafa
authors.initials: M
authors.lastname: Hassan
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Walsh
authors.forename: Ehab
authors.initials: E
authors.lastname: Al-Moubarak
authors.forename: Alistair
authors.initials: A
authors.lastname: Mathie
mesh_terms: D002460:Cell Line; D019465:Craniofacial Abnormalities / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism; D008564:Membrane Potentials / Q000235:genetics; D009123:Muscle Hypotonia / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics* / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000235:genetics / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
chemical_list: C498655:KCNK9 protein, human; D015221:Potassium Channels; D024683:Potassium Channels, Tandem Pore Domain; D043587:Receptor, Muscarinic M3; D015032:Zinc