title: Enhancement of TWIK-related acid-sensitive potassium channel 3 (TASK3) two-pore domain potassium channel activity by tumor necrosis factor α.
abstract: 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.
authors.affiliation: From the Medway School of Pharmacy, University of Kent, Central Avenue, Chatham Maritime, ME4 4TB Kent, United Kingdom.
authors.forename: Mickael-F
authors.initials: MF
authors.lastname: El Hachmane
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Rees
authors.forename: Emma L
authors.initials: EL
authors.lastname: Veale
authors.forename: Vadim V
authors.initials: VV
authors.lastname: Sumbayev
authors.forename: Alistair
authors.initials: A
authors.lastname: Mathie
mesh_terms: D000263:Adenylate Kinase / Q000235:genetics / Q000378:metabolism; D019943:Amino Acid Substitution; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D018920:Coculture Techniques; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D020125:Mutation, Missense; D024683:Potassium Channels, Tandem Pore Domain / Q000096:biosynthesis* / Q000235:genetics; D017434:Protein Structure, Tertiary; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D007093:Imidazoles; C498655:KCNK9 protein, human; D024683:Potassium Channels, Tandem Pore Domain; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D000263:Adenylate Kinase; C110939:adenylate kinase 1; C402365:resiquimod
keywords: Apoptosis; Ion Channels; Jun N-terminal Kinase (JNK); Patch Clamp Electrophysiology; Potassium Channels; Tumor Necrosis Factor (TNF); p38