TNFα enhances TASK3 potassium channel current in a model of inflammation

Tumour Necrosis Factor α (TNFα) mediated regulation of neuronal activity and ionic homeostasis, through modulation of ion channels, may contribute to its action in various phenomena, such as neuronal inflammation, cell death and neuropathic nociception. In this study we consider the effect of TNFα on the two‐pore domain K channel, TASK3, using tsA‐201 cells transfected with TASK3 cDNA and whole cell patch clamp recordings. Following a 2hr incubation, TNFα (10ng/mL) enhanced TASK3 current from 68 ± 7 pA/pF (n = 9) to 103 ± 6 pA/pF (n = 10). Mutation of two individual phosphorylation sites present on the C‐terminus of TASK3, S319A and S331A, abolished the TNFα effect, showing that TASK3 C‐terminal phosphorylation is required for the enhancement. An analysis of the transduction pathway highlighted ASK1 and one of its downstream kinases, JNK, as mediators of the TNFα effect on TASK3. To recapitulate the role of TNFα in the inflammation process, we co‐cultured tsA‐201 cells with human myeloid THP‐1 cells and activated the latter with R848, a Toll‐like receptor 7/8 – specific ligand. Activated THP‐1 cells enhanced significantly the TASK3 current in tsA‐201 cells but this effect was inhibited when cells were pre‐incubated with a TNFα‐neutralising antibody. Our results show that TNFα can upregulate TASK3 channel currents and suggests that this mechanism may underlie the actions of TNFα in neuronal inflammation.