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

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 Gα q/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)P 2 nor release of the downstream messengers IP 3 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. TASK-1 and -3 are members of the two-pore domain K + channel family that play important roles in the regulation of cellular excitability. Here, Wilke et al. demonstrate that the second messenger lipid diacylglycerol (DAG) gates TASK1/3, defining a new role for DAG in controlling the dynamics of cellular excitability.