Antagonistic Effect of a Cytoplasmic Domain on the Basal Activity of Polymodal Potassium Channels
Résumé
TREK/TRAAK channels are polymodal K+ channels that convert very diverse stimuli,
including bioactive lipids, mechanical stretch and temperature, into electrical signals.
The nature of the structural changes that regulate their activity remains an open
question. Here, we show that a cytoplasmic domain (the proximal C-ter domain, pCt)
exerts antagonistic effects in TREK1 and TRAAK. In basal conditions, pCt favors activity
in TREK1 whereas it impairs TRAAK activity. Using the conformation-dependent binding
of fluoxetine, we show that TREK1 and TRAAK conformations at rest are different, and
under the influence of pCt. Finally, we show that depleting PIP2 in live cells has a more
pronounced inhibitory effect on TREK1 than on TRAAK. This differential regulation of
TREK1 and TRAAK is related to a previously unrecognized PIP2-binding site (R329,
R330, and R331) present within TREK1 pCt, but not in TRAAK pCt. Collectively, these
new data point out pCt as a major regulatory domain of these channels and suggest
that the binding of PIP2 to the pCt of TREK1 results in the stabilization of the conductive
conformation in basal conditions.