TWIK-related acid sensitive K+ (TASK) channels belong to the K2P channel family and contribute significantly to the background conductance in various cell types, e.g. to IK,SO in cerebellar granule cells. It is known that stimulation of Gq-protein coupled receptors (GqPCRs) causes strong and reversible inhibition of TASK channels. Yet, the underlying signaling cascade is still controversial: Both, the inhibition of TASK by Gαq-protein via a direct molecular interaction, or, alternatively, by signals downstream of phospholipase C (PLC) activation have been proposed. PLC mediates the hydrolysis of phosphoinositide-4,5-bisphosphate (PI(4,5)P2), thereby producing the second messengers diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (IP3). Here, we examine the requirement of PLC in GqPCR-signaling for TASK-inhibition.Whole cell patch clamp experiments were performed on CHO cells expressing TASK3 channels while PLC activity was modulated pharmacologically. PLC was activated through the application of the PLC-activator m-3M3FBS causing TASK3 current suppression. In contrast, Gq-mediated TASK3 inhibition by activation of muscarinic M1 receptor was abolished by the PLC inhibitor U73122. The efficiency of both pharmacological manipulations of PLC was verified with the DAG-sensor PKCγ-C1 and the PI(4,5)P2-sensor PLCδ1-PH, monitored in total internal reflection fluorescence microscopy.These data suggest that activation of PLC is an indispensable step in GqPCR – TASK signaling and are inconsistent with the hypothesis that direct Gαq-interaction mediates TASK current inhibition.This work was supported by DFG grant OL 240/3-1 (FOR 1086) to DO.Chen, X. et al., 2006, PNAS 103, 3422-7.Chemin, J. et al., 2003, EMBO J. 22, 5403-11.Lindner, M. et al., 2011, J. Physiol. 589, 3149-62.