The versatile regulation of K(2P) channels by polyanionic lipids of the phosphoinositide and fatty acid metabolism

Work over the past three decades has greatly advanced our understanding of the regulation of K(ir) K(+) 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 regulation of the K(2P) channel family by phosphoinositides and by long-chain fatty acid–CoA esters, such as oleoyl-CoA. We screened 12 mammalian K(2P) channels and report effects of polyanionic lipids on all tested channels. We observed activation of members of the TREK, TALK, and THIK subfamilies, with the strongest activation by PIP(2) for TRAAK and the strongest activation by oleoyl-CoA for TALK-2. By contrast, we observed inhibition for members of the TASK and TRESK subfamilies. Our results reveal that TASK-2 channels have both activatory and inhibitory PIP(2) sites with different affinities. Finally, we provided evidence that PIP(2) inhibition of 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 findings establish that K(+) channels of the K(2P) family are highly sensitive to polyanionic lipids, extending our knowledge of the mechanisms of lipid regulation and implicating the metabolism of these lipids as possible effector pathways to regulate K(2P) channel activity.