The versatile regulation of K_2P channels by polyanionic lipids of the phosphoinositide (PIP₂) and fatty acid metabolism (LC-CoA)

Work of the past three decades provided tremendous insight into the regulation of K⁺ channels - in particular K_ir channels - by polyanionic lipids of the phosphoinositide (e.g. PIP₂) and fatty acid metabolism (e.g. oleoyl-CoA). However, comparatively little is known regarding the phosphoinositide regulation in the K_2P channel family and the effects of long-chain fatty acid CoA esters (LC-CoA, e.g. oleoyl-CoA) are so far unexplored. By screening most mammalian K_2P channels (12 in total), we report strong effects of polyanionic lipids (activation and inhibition) for all tested K_2P channels. In most cases the effects of PIP₂ and oleoyl-CoA were similar causing either activation or inhibition depending on the respective subgroup. Activation was observed for members of the TREK, TALK and THIK subfamily with the strongest activation by PIP₂ seen for TRAAK (~110-fold) and by oleoyl-CoA for TALK-2 (~90-fold). In contrast, inhibition was observed for members of the TASK and TRESK subfamilies up to ~85 %. In TASK-2 channels our results indicated an activatory as well as an inhibitory PIP₂ site with different affinities. Finally, we provided evidence that PIP₂ inhibition in TASK-1 and TASK-3 channels is mediated by closure of the recently identified lower X-gate as critical mutations within the gate (i.e. L244A, R245A) prevent PIP₂ induced inhibition. Our results disclosed K_2P channels as a family of ion channels highly sensitive to polyanionic lipids (PIP₂ and LC-CoA), extended our knowledge on the mechanisms of lipid regulation and implicate the metabolisms of these lipids as possible effector pathways to regulate K_2P channel activity.