title: Diacylglycerol mediates regulation of TASK potassium channels by Gq-coupled receptors.
abstract: The two-pore domain potassium (K2P) channels TASK-1 (KCNK3) and TASK-3 (KCNK9) are important determinants of background K(+) conductance and membrane potential. TASK-1/3 activity is regulated by hormones and transmitters that act through G protein-coupled receptors (GPCR) signalling via G proteins of the Gαq/11 subclass. How the receptors inhibit channel activity has remained unclear. Here, we show that TASK-1 and -3 channels are gated by diacylglycerol (DAG). Receptor-initiated inhibition of TASK required the activity of phospholipase C, but neither depletion of the PLC substrate PI(4,5)P2 nor release of the downstream messengers IP3 and Ca(2+). Attenuation of cellular DAG transients by DAG kinase or lipase suppressed receptor-dependent inhibition, showing that the increase in cellular DAG-but not in downstream lipid metabolites-mediates channel inhibition. The findings identify DAG as the signal regulating TASK channels downstream of GPCRs and define a novel role for DAG that directly links cellular DAG dynamics to excitability.
authors.affiliation: Institute of Physiology and Pathophysiology, Department of Neurophysiology, Philipps University, Deutschhausstr. 1-2, 35037 Marburg, Germany.
authors.forename: Bettina U
authors.initials: BU
authors.lastname: Wilke
authors.affiliation: Institute of Physiology and Pathophysiology, Department of Neurophysiology, Philipps University, Deutschhausstr. 1-2, 35037 Marburg, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Lindner
authors.affiliation: Institute of Physiology and Pathophysiology, Department of Neurophysiology, Philipps University, Deutschhausstr. 1-2, 35037 Marburg, Germany.
authors.forename: Lea
authors.initials: L
authors.lastname: Greifenberg
authors.affiliation: Institute of Physiology and Pathophysiology, Department of Neurophysiology, Philipps University, Deutschhausstr. 1-2, 35037 Marburg, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Albus
authors.affiliation: Institute of Physiology and Pathophysiology, Department of Neurophysiology, Philipps University, Deutschhausstr. 1-2, 35037 Marburg, Germany.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Kronimus
authors.affiliation: Department of Pharmacology and Clinical Pharmacy, Philipps University, 35032 Marburg, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Bünemann
authors.affiliation: Institute of Physiology and Pathophysiology, Department of Neurophysiology, Philipps University, Deutschhausstr. 1-2, 35037 Marburg, Germany.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Leitner
authors.affiliation: Institute of Physiology and Pathophysiology, Department of Neurophysiology, Philipps University, Deutschhausstr. 1-2, 35037 Marburg, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Oliver
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004075:Diglycerides / Q000378:metabolism*; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics / Q000378:metabolism*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D024683:Potassium Channels, Tandem Pore Domain / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism
chemical_list: C011439:1,2-diacylglycerol; D004075:Diglycerides; C554061:GNAQ protein, human; D044385:GTP-Binding Protein alpha Subunits; C498655:KCNK9 protein, human; D009419:Nerve Tissue Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D024683:Potassium Channels, Tandem Pore Domain; C420132:potassium channel subfamily K member 3; D015544:Inositol 1,4,5-Trisphosphate; D011493:Protein Kinase C; D010738:Type C Phospholipases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D002118:Calcium