Phospholipase D2 specifically regulates TREK potassium channels via direct interaction and local production of phosphatidic acid

Proc Natl Acad Sci U S A. 2014 Sep 16;111(37):13547-52. doi: 10.1073/pnas.1407160111. Epub 2014 Sep 2.


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

Keywords: K2P2.1; alcohol; micro-regulatory domain; neuron excitability; potassium channels.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alcohols / pharmacology
  • Amino Acids / metabolism
  • Biocatalysis / drug effects
  • Domperidone / analogs & derivatives
  • Domperidone / pharmacology
  • Enzyme Inhibitors / pharmacology
  • HEK293 Cells
  • Hippocampus / cytology
  • Humans
  • Indoles / pharmacology
  • Ion Channel Gating / drug effects
  • Models, Biological
  • Mutant Proteins / metabolism
  • Neurons / drug effects
  • Neurons / metabolism
  • Phosphatidic Acids / metabolism*
  • Phospholipase D / antagonists & inhibitors
  • Phospholipase D / metabolism*
  • Potassium Channels / metabolism
  • Potassium Channels, Tandem Pore Domain / chemistry
  • Potassium Channels, Tandem Pore Domain / metabolism*
  • Protein Binding / drug effects


  • 5-fluoro-2-indolyldeschlorohalopemide
  • Alcohols
  • Amino Acids
  • Enzyme Inhibitors
  • Indoles
  • KCNK10 protein, human
  • KCNK4 protein, human
  • Mutant Proteins
  • Phosphatidic Acids
  • Potassium Channels
  • Potassium Channels, Tandem Pore Domain
  • potassium channel protein TREK-1
  • Domperidone
  • phospholipase D2
  • Phospholipase D
  • phospholipase D1