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

Honoré, Eric; Maingret, François; Lazdunski, Michel; Patel, Amanda Jane
June 2002
EMBO Journal;6/15/2002, Vol. 21 Issue 12, p2968
Academic Journal
The 2P domain K+ channel TREK-1 is widely expressed 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-i 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-i 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 toss-of-function truncated TREK-1 mutant. We conclude that protonation of E306 tunes the TREK-i mechanical setpoint and thus sets lipid sensitivity.


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