The versatile regulation of K2P 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. PIP 2 ) 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 PIP 2 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 PIP 2 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 PIP 2 site with different affinities. Finally, we provided evidence that PIP 2 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 PIP 2 induced inhibition. Our results disclosed K 2P channels as a family of ion channels highly sensitive to polyanionic lipids (PIP 2 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.