An intracellular proton sensor commands lipid- and mechano-gating of the K(+) channel TREK-1

EMBO J. 2002 Jun 17;21(12):2968-76. doi: 10.1093/emboj/cdf288.


The 2P domain K(+) channel TREK-1 is widely expres sed in the nervous system. It is opened by a variety of physical and chemical stimuli including membrane stretch, intracellular acidosis and polyunsaturated fatty acids. This activation can be reversed by PKA-mediated phosphorylation. The C-terminal domain of TREK-1 is critical for its polymodal function. We demonstrate that the conversion of a specific glutamate residue (E306) to an alanine in this region locks TREK-1 in the open configuration and abolishes the cAMP/PKA down-modulation. The E306A substitution mimics intracellular acidosis and rescues both lipid- and mechano-sensitivity of a loss-of-function truncated TREK-1 mutant. We conclude that protonation of E306 tunes the TREK-1 mechanical setpoint and thus sets lipid sensitivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Cyclic AMP / analogs & derivatives
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Glutamic Acid / genetics
  • Hydrogen-Ion Concentration
  • Ion Channel Gating / physiology*
  • Models, Biological
  • Mutagenesis, Site-Directed
  • Patch-Clamp Techniques
  • Phosphorylation
  • Potassium Channels / chemistry
  • Potassium Channels / genetics
  • Potassium Channels / metabolism*
  • Potassium Channels, Tandem Pore Domain*
  • Protein Structure, Secondary
  • Protein Structure, Tertiary


  • Potassium Channels
  • Potassium Channels, Tandem Pore Domain
  • potassium channel protein TREK-1
  • Glutamic Acid
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases