Diacylglycerol mediates regulation of TASK potassium channels by Gq-coupled receptors

Nat Commun. 2014 Nov 25;5:5540. doi: 10.1038/ncomms6540.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Calcium / metabolism
  • Cell Line
  • Diglycerides / metabolism*
  • GTP-Binding Protein alpha Subunits / genetics
  • GTP-Binding Protein alpha Subunits / metabolism*
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • Humans
  • Inositol 1,4,5-Trisphosphate / metabolism
  • Mice
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Phosphatidylinositol 4,5-Diphosphate / metabolism
  • Potassium Channels, Tandem Pore Domain / chemistry
  • Potassium Channels, Tandem Pore Domain / genetics
  • Potassium Channels, Tandem Pore Domain / metabolism*
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism
  • Signal Transduction
  • Type C Phospholipases / genetics
  • Type C Phospholipases / metabolism

Substances

  • 1,2-diacylglycerol
  • Diglycerides
  • GNAQ protein, human
  • GTP-Binding Protein alpha Subunits
  • KCNK9 protein, human
  • Nerve Tissue Proteins
  • Phosphatidylinositol 4,5-Diphosphate
  • Potassium Channels, Tandem Pore Domain
  • potassium channel subfamily K member 3
  • Inositol 1,4,5-Trisphosphate
  • Protein Kinase C
  • Type C Phospholipases
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • Calcium