The versatile regulation of K2P channels by polyanionic lipids of the phosphoinositide (PIP2) and fatty acid metabolism (LC-CoA)

Abstract

Work of the past three decades provided tremendous insight into the regulation of K+ channels - in particular Kir 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 K2P 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 K2P channels (12 in total), we report strong effects of polyanionic lipids (activation and inhibition) for all tested K2P 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 K2P 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 K2P channel activity.