Phospholipase D2 Specifically Regulates Trek Channels Via Direct Interaction And Local Production Of Phosphatidic Acid

Membrane lipids serve as second messengers and docking sites for proteins and play central roles in cell signalling. A major question about lipid signaling is whether diffusible lipids can selectively target specific proteins. One family of lipid-regulated membrane proteins is the TREK subfamily of K2P channels: TREK1, TREK2, and TRAAK. We investigated the regulation of TREK channels by phosphatidic acid (PA), which is generated by Phospholipase D (PLD) via hydrolysis of phosphatidylcholine. We found that, even though all three of the channels are sensitive to PA, only TREK1 and TREK2 are potentiated by PLD2 and that none of these channels is modulated by PLD1, indicating surprising selectivity. We find that PLD2, but not PLD1, directly binds to the C-terminus of TREK1 and TREK2, but not to TRAAK. The results lead to a model for selective lipid regulation by localization of phospholipid enzymes to specific effector proteins. Finally, by using the photoswitchable conditionnal subunit method to endow light sensitivity to the native TREK1 channels, we show that regulation of TREK channels by PLD2 occurs natively in hippocampal neurons.