Regulation of K+ channels by phosphoinositides (PIPs) is a characteristic of many of the members of this large superfamily of proteins, but whether the same applies to those belonging to the two-P domain in tandem K2P clade, has been controversial. TASK-2 is a member of the K2P channel family with important functions in the kidney and chemosensitive neurons (López-Cayuqueo et al., 2015). Here we have investigated the possible regulation of TASK-2 activity by membrane PIPs. K+ currents in HEK-293 cells expressing recombinant TASK-2 were measured in whole cell or inside-out isolated patches. Whole-cell currents are stable in the presence of intracellular ATP but rapidly rundown in its absence, upon replacement with a non-hydrolysable ATP analogue or in the presence of polycation scavengers of PIPs such as neomycin. Activation of a coexpressed voltage-sensitive phosphatase from Danio rerio (DrVSP), that removes 5-phosphate groups from PI(4,5)P2, also led to a marked inhibition of TASK-2 current. This was reversible but only in the presence of Mg2+ suggesting an endogenous kinase activity involvement. Activation of Gq-coupled receptors is accompanied by membrane PI(4,5)P2 depletion.Consistent with a sensitivity to PI(4,5)P2, TASK-2 channels expressed with angiotensin II AT1 receptors were markedly inhibited by receptor stimulation. Diacylglycerol addition had only a minor effect, suggesting it is not the main drive behind AT1-dependent inhibition of TASK-2. TASK-2 rundown in excised membrane patches in the absence of ATP could be restored by intracellular addition of PI(4,5)P2 or other PIPs tested in their soluble DiC8 form. Largest effect was obtained with PI(3,4,5)P3 while that of PI(4)P was quite small. EC50 values ranked in the order PI(3,4,5)P3 < PI(4,5)P2 < PI(3,4)P2 < PI(4)P. The interaction between PIPs and the proteins they regulate have been shown to be electrostatic and occur through interactions with basic residues. TASK-2 positively charged residues facing intracellularly were systematically replaced one at a time by cysteines to disable interaction and inhibit activity. Cysteines can be charged positively using small methanethiosulfonate reagents such as (2-(trimethylammonium)ethyl)methanethiosulfonate (MTSET) thus restoring interaction. Of the 45 mutants, only two, K254C and K297C, were significantly activated after MTSET treatment suggesting they are involved in the regulation of TASK-2 by PIPs. Screening the same mutants using the kinetics of inhibition of TASK-2 by DrVSP revealed a third residue, R438, that might also be involved in the interaction. Our results suggest that TASK-2 is under the regulation of PIPs, of which the main plasma membrane representative is PI(4,5)P2, through an interaction with basic residues of its C-terminus. This modulation might be of relevance to the physiological roles of TASK-2.