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Enhancement of TWIK-related acid-sensitive potassium channel 3 (TASK3) two-pore domain potassium channel activity by tumor necrosis factor α

El Hachmane, Mickael-F., Rees, Kathryn A., Veale, Emma L., Sumbayev, Vadim V., Mathie, Alistair (2014) Enhancement of TWIK-related acid-sensitive potassium channel 3 (TASK3) two-pore domain potassium channel activity by tumor necrosis factor α. The Journal of Biological Chemistry, 289 (3). pp. 1388-1401. ISSN 0021-9258. E-ISSN 1083-351X. (doi:10.1074/jbc.M113.500033) (KAR id:75885)

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TASK3 two-pore domain potassium (K2P) channels are responsible for native leak K channels in many cell types which regulate cell resting membrane potential and excitability. In addition, TASK3 channels contribute to the regulation of cellular potassium homeostasis. Because TASK3 channels are important for cell viability, having putative roles in both neuronal apoptosis and oncogenesis, we sought to determine their behavior under inflammatory conditions by investigating the effect of TNFα on TASK3 channel current. TASK3 channels were expressed in tsA-201 cells, and the current through them was measured using whole cell voltage clamp recordings. We show that THP-1 human myeloid leukemia monocytes, co-cultured with hTASK3-transfected tsA-201 cells, can be activated by the specific Toll-like receptor 7/8 activator, R848, to release TNFα that subsequently enhances hTASK3 current. Both hTASK3 and mTASK3 channel activity is increased by incubation with recombinant TNFα (10 ng/ml for 2-15 h), but other K2P channels (hTASK1, hTASK2, hTREK1, and hTRESK) are unaffected. This enhancement by TNFα is not due to alterations in levels of channel expression at the membrane but rather to an alteration in channel gating. The enhancement by TNFα can be blocked by extracellular acidification but persists for mutated TASK3 (H98A) channels that are no longer acid-sensitive even in an acidic extracellular environment. TNFα action on TASK3 channels is mediated through the intracellular C terminus of the channel. Furthermore, it occurs through the ASK1 pathway and is JNK- and p38-dependent. In combination, TNFα activation and TASK3 channel activity can promote cellular apoptosis.

Item Type: Article
DOI/Identification number: 10.1074/jbc.M113.500033
Subjects: Q Science
Divisions: Divisions > Division of Natural Sciences > Medway School of Pharmacy
Depositing User: Emma Veale
Date Deposited: 19 Aug 2019 21:57 UTC
Last Modified: 16 Feb 2021 14:06 UTC
Resource URI: (The current URI for this page, for reference purposes)
Veale, Emma L.:
Sumbayev, Vadim V.:
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