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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.

Original publication

DOI

10.1038/ncomms6540

Type

Journal article

Journal

Nat Commun

Publication Date

25/11/2014

Volume

5

Keywords

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