Antagonistic Effect of a Cytoplasmic Domain on the Basal Activity of Polymodal Potassium Channels

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Soussia, Ismail Ben | Choveau, Frank | Blin, Sandy | Kim, Eun-Jin | Feliciangeli, Sylvain | Chatelain, Franck | Kang, Dawon | Bichet, Delphine | Lesage, Florian

Edité par CCSD ; Frontiers Media -

International audience. 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 openquestion. 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 activityin TREK1 whereas it impairs TRAAK activity. Using the conformation-dependent bindingof fluoxetine, we show that TREK1 and TRAAK conformations at rest are different, andunder the influence of pCt. Finally, we show that depleting PIP2 in live cells has a morepronounced inhibitory effect on TREK1 than on TRAAK. This differential regulation ofTREK1 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, thesenew data point out pCt as a major regulatory domain of these channels and suggestthat the binding of PIP2 to the pCt of TREK1 results in the stabilization of the conductiveconformation in basal conditions.

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