Phosphatidylinositol (4,5)-bisphosphate dynamically regulates the K(2P) background K(+) channel TASK-2

Two-pore domain K(2P) K(+) channels responsible for the background K(+) conductance and the resting membrane potential, are also finely regulated by a variety of chemical, physical and physiological stimuli. Hormones and transmitters acting through Gq protein-coupled receptors (GqPCRs) modulate the activity of various K(2P) channels but the signalling involved has remained elusive, in particular whether dynamic regulation by membrane PI(4,5)P(2), common among other classes of K(+) channels, affects K(2P) channels is controversial. Here we show that K(2P) K(+) channel TASK-2 requires PI(4,5)P(2) for activity, a dependence that accounts for its run down in the absence of intracellular ATP and its full recovery by addition of exogenous PI(4,5)P(2), its inhibition by low concentrations of polycation PI scavengers, and inhibition by PI(4,5)P(2) depletion from the membrane. Comprehensive mutagenesis suggests that PI(4,5)P(2) interaction with TASK-2 takes place at C-terminus where three basic aminoacids are identified as being part of a putative binding site.