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)P₂, 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)P₂ 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)P₂, its inhibition by low concentrations of polycation PI scavengers, and inhibition by PI(4,5)P₂ depletion from the membrane. Comprehensive mutagenesis suggests that PI(4,5)P₂ interaction with TASK-2 takes place at C-terminus where three basic aminoacids are identified as being part of a putative binding site.