Structural Basis For Gating Of The Two-Pore Domain K+ (K-2p) Channels Task-1 And Talk-2

Two-pore domain K+ (K2P) channel activity is controlled by various stimuli that have been thought to finally converge at the selectivity filter (SF) gate. However, recent crystallographic studies have identified lower gates in TASK-1 and TASK-2 K2P channels but pharmacological means to open these gates are currently unknown. Here, we report that TALK-2 K2P channels also possess a lower gate by utilizing scanning mutagenesis, pore blocker analysis, permeant ion effects, chemical modification and MD simulations. Moreover, we report small molecule drugs and cellular lipids including long chain fatty acid esters (LC-CoAs) that open the lower gates in homomeric TASK-1, TALK-2 and TASK-1/TALK-2 heteromeric K2P channels. Intriguingly, one of these openers is the pulmonary arterial hypertension (PAH) antidote ONO-RS-082 acting on PAH disease-gen TASK-1. Our results suggest that ONO-RS-082 open the lower gates by binding to the pore cavity when the lower gates are open which bears major implications for future design of PAH drugs. Finally, our results suggest a classification in the K2P channel family with channels that exclusively utilize the SF gate (e.g. TREK-1/-2 and TRAAK), channels that exclusively utilize the lower gate (e.g. TASK-1) and K2P channels with two functional gates (e.g. TALK-2 and TASK-2) highlighting the unusual diversity in structural gating mechanisms within this K+ channel family.