PT  - JOURNAL ARTICLE
AU  - Emma L Veale
AU  - Mustafa Hassan
AU  - Yvonne Walsh
AU  - Ehab Al Moubarak
AU  - Alistair Mathie
TI  - Genetic and Pharmacological Recovery of Current in Mutated TASK3 Potassium Channels Underlying Birk Barel Mental Retardation Syndrome
AID  - 10.1124/mol.113.090530
DP  - 2013 Jan 01
TA  - Molecular Pharmacology
PG  - mol.113.090530
4099  - http://molpharm.aspetjournals.org/content/early/2013/12/16/mol.113.090530.short
4100  - http://molpharm.aspetjournals.org/content/early/2013/12/16/mol.113.090530.full
AB  - TASK3 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 a maternally transmitted developmental disorder, Birk Barel mental retardation dysmorphism syndrome. This syndrome may arise from a neuronal migration defect during development caused by dysfunctional TASK3 channels. Through the use of whole-cell electrophysiological 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 to 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 non-steroidal anti-inflammatory drug, flufenamic acid. Flufenamic acid produces a significantly greater enhancement of current through mutated channels than through WT TASK3 channels. We propose that pharmacological enhancement of mutated TASK3 channel current during development may, therefore, provide a potentially useful therapeutic strategy in the treatment of Birk Barel syndrome.