Influence of the N terminus on the biophysical properties and pharmacology of TREK1 potassium channels

Mol Pharmacol. 2014 May;85(5):671-81. doi: 10.1124/mol.113.091199. Epub 2014 Feb 7.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Fenamates / pharmacology*
  • HEK293 Cells
  • Humans
  • Ion Channel Gating / drug effects
  • Ion Channel Gating / physiology
  • Mutation / physiology
  • Potassium Channels, Tandem Pore Domain / agonists*
  • Potassium Channels, Tandem Pore Domain / chemistry
  • Potassium Channels, Tandem Pore Domain / physiology*
  • Protein Structure, Secondary

Substances

  • Fenamates
  • Potassium Channels, Tandem Pore Domain
  • potassium channel protein TREK-1