title: Phospholipase D2 specifically regulates TREK potassium channels via direct interaction and local production of phosphatidic acid.
abstract: 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.
authors.affiliation: Université Nice Sophia Antipolis, Institut de Biologie Valrose, Unité Mixte de Recherche 7277, 06100 Nice, France; Centre National de la Recherche Scientifique, Institut de Biologie Valrose, Unité Mixte de Recherche 7277, 06100 Nice, France; Institut National de la Santé et de la Recherche Médicale, Institut de Biologie Valrose, U1091, 06100 Nice, France; Laboratories of Excellence, Ion Channel Science and Therapeutics, 06100 Nice, France;
authors.forename: Yannick
authors.initials: Y
authors.lastname: Comoglio
authors.affiliation: Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94720; Biophysics Graduate Group, University of California, Berkeley, CA 94720;
authors.forename: Joshua
authors.initials: J
authors.lastname: Levitz
authors.affiliation: Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94720;
authors.forename: Michael A
authors.initials: MA
authors.lastname: Kienzler
authors.affiliation: Université Nice Sophia Antipolis, Institut de Biologie Valrose, Unité Mixte de Recherche 7277, 06100 Nice, France; Laboratories of Excellence, Ion Channel Science and Therapeutics, 06100 Nice, France; Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, and Université Nice Sophia Antipolis, Sophia-Antipolis, 06560 Valbonne, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Lesage
authors.affiliation: Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94720; Biophysics Graduate Group, University of California, Berkeley, CA 94720; Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94703; and.
authors.forename: Ehud Y
authors.initials: EY
authors.lastname: Isacoff
authors.affiliation: Université Nice Sophia Antipolis, Institut de Biologie Valrose, Unité Mixte de Recherche 7277, 06100 Nice, France; Centre National de la Recherche Scientifique, Institut de Biologie Valrose, Unité Mixte de Recherche 7277, 06100 Nice, France; Institut National de la Santé et de la Recherche Médicale, Institut de Biologie Valrose, U1091, 06100 Nice, France; Laboratories of Excellence, Ion Channel Science and Therapeutics, 06100 Nice, France; sandoz@unice.fr.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Sandoz
mesh_terms: D000438:Alcohols / Q000494:pharmacology; D000596:Amino Acids / Q000378:metabolism; D055162:Biocatalysis / Q000187:drug effects; D004294:Domperidone / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010712:Phosphatidic Acids / Q000378:metabolism*; D010739:Phospholipase D / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism; D024683:Potassium Channels, Tandem Pore Domain / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects
chemical_list: C546435:5-fluoro-2-indolyldeschlorohalopemide; D000438:Alcohols; D000596:Amino Acids; D004791:Enzyme Inhibitors; D007211:Indoles; C503438:KCNK10 protein, human; C503432:KCNK4 protein, human; D050505:Mutant Proteins; D010712:Phosphatidic Acids; D015221:Potassium Channels; D024683:Potassium Channels, Tandem Pore Domain; C103742:potassium channel protein TREK-1; D004294:Domperidone; C105606:phospholipase D2; D010739:Phospholipase D; C106801:phospholipase D1
keywords: K2P2.1; alcohol; micro-regulatory domain; neuron excitability; potassium channels