Endothelial TWIK-related potassium channel-1 (TREK1) regulates immune-cell trafficking into the CNS

  • Meadows H
  • Benham C
  • Cairns W
 et al. 
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TWIK-related K(+) 1 (TREK1) potassium channels are members of the two-pore domain potassium channel family and contribute to background potassium conductances in many cell types, where their activity can be regulated by a variety of physiologic and pharmacologic mediators. Fenamates such as FFA (flufenamic acid; 2-{[3-(trifluoromethyl)phenyl]amino}benzoic acid), MFA [mefenamic acid; 2-(2,3-dimethylphenyl)aminobenzoic acid], NFA [niflumic acid; 2-{[3-(trifluoromethyl)phenyl]amino}nicotinic acid], and diclofenac [2-(2-(2,6-dichlorophenylamino)phenyl)acetic acid] and the related experimental drug BL-1249 [(5,6,7,8-tetrahydro-naphthalen-1-yl)-[2-(1H-tetrazol-5-yl)-phenyl]-amine] enhance the activity of TREK1 currents, and we show that BL-1249 is the most potent of these compounds. Alternative translation initiation produces a shorter, N terminus truncated form of TREK1 with a much reduced open probability and a proposed increased permeability to sodium compared with the longer form. We show that both forms of TREK1 can be activated by fenamates and that a number of mutations that affect TREK1 channel gating occlude the action of fenamates but only in the longer form of TREK1. Furthermore, fenamates produce a marked enhancement of current through the shorter, truncated form of TREK1 and reveal a K(+)-selective channel, like the long form. These results provide insight into the mechanism of TREK1 channel activation by fenamates, and, given the role of TREK1 channels in pain, they suggest a novel analgesic mechanism for these compounds.

Author-supplied keywords

  • -adrenergic receptor ⅲ heart
  • 119
  • 14-3-3
  • 2010
  • 2011
  • 27
  • 39
  • Amino Acid Sequence
  • Amino Acid Sequence: genetics
  • Animals
  • Base Sequence
  • Base Sequence: genetics
  • Cell Line
  • Cloning
  • Fenamates
  • Fenamates: pharmacology
  • HEK293 Cells
  • Humans
  • Ion Channel Gating
  • Ion Channel Gating: drug effects
  • Ion Channel Gating: physiology
  • Mice
  • Molecular
  • Molecular Sequence Data
  • Mutation
  • Mutation: physiology
  • Oocytes
  • Oocytes: metabolism
  • Peptide Fragments
  • Peptide Fragments: metabolism
  • Peptide Fragments: physiology
  • Potassium Channels
  • Potassium Channels: genetics
  • Potassium Channels: metabolism
  • Protein Structure
  • Secondary
  • Tandem Pore Domain
  • Tandem Pore Domain: agonists
  • Tandem Pore Domain: chemistry
  • Tandem Pore Domain: physiology
  • Tissue Distribution
  • Xenopus laevis
  • Xenopus laevis: metabolism
  • a -amino-3-hydroxy-5-methyl-isoxazole-4-propionic
  • ampa receptors
  • and ventricular
  • anesthetics ⅲ
  • anxiety
  • ardiac potassium
  • behavior
  • cells
  • channel
  • channels are thought to
  • channels have extensively been
  • conductance in many cell
  • cortical contusion injury
  • czirjak
  • e3 ligase
  • endoplasmic reticulum
  • enyedi and
  • family is diverse
  • following two major families
  • glutamate receptors
  • in the working atrial
  • j
  • k 2p
  • k ϩ
  • kcnk2
  • knockout
  • memory
  • morphine
  • myocytes
  • nedd4
  • neurochem
  • neuronal
  • neuroprotection
  • p11
  • potassium channel
  • potassium channels
  • potassium channels ⅲ volatile
  • studied for years
  • task
  • the background k
  • the k 2p channel
  • they belong to the
  • trafficking
  • trek
  • two pore domain potassium
  • two-pore domain k
  • two-pore domain potassium
  • types
  • ubiquitination
  • underlie
  • with six sub-

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  • H J Meadows

  • C D Benham

  • W Cairns

  • I Gloger

  • C Jennings

  • a D Medhurst

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