A lower X-gate in TASK channels traps inhibitors within the vestibule

Abstract

TASK channels are unusual members of the two-pore domain potassium (K2P) channel family, found in neurons 1 , cardiomyocytes 2-4 and vascular smooth muscle cells 5 where they are involved in regulation of heart rate 6 , pulmonary artery tone 5,7 , sleep/wake cycles 8 and responses to volatile anaesthetics 8-11. K2P channels regulate the resting membrane potential, providing background K + currents controlled by numerous physiological stimuli 12-15. Unlike other K2P channels, TASK channels have the capacity to bind inhibitors with high affinity, exceptional selectivity and very slow compound washout rates. These characteristics make TASK channels some of the most easily druggable potassium channels, and indeed TASK-1 inhibitors are currently in clinical trials for obstructive sleep apnea (OSA) and atrial fibrillation (Afib) 16 (the DOCTOS and SANDMAN trials). Generally, potassium channels have an intramembrane vestibule with a selectivity filter above and a gate with four parallel helices below. However, K2P channels studied to date all lack a lower gate. Here we present the structure of TASK-1, revealing a lower gate created by interaction of the two crossed C-terminal M4 transmembrane helices at the vestibule entrance, which we designate as an "X-gate". This structure is formed by six residues (V 243 LRFMT 248) that are essential for responses to volatile anaesthetics 10 , neuro-transmitters 13 and G-protein coupled receptors 13. Interestingly, mutations within the X-gate and surrounding regions drastically affect both open probability and activation by anaesthetics. Structures of TASK-1 with two novel, highaffinity blockers, show both inhibitors bound below the selectivity filter, trapped in the vestibule by the X-gate, thus explaining their exceptionally low wash-out rates. Thus, the presence of the X-gate in TASK channels explains many aspects of their unusual physiological and pharmacological behaviour, which is invaluable for future development and optimization of TASK modulators for treatment of heart, lung and sleep disorders.

Current Drug Treatment Strategies for Atrial Fibrillation and TASK-1 Inhibition as an Emerging Novel Therapy Option

“…TASK-1 binds its inhibitors highly selective, with strong affinity and extremely low washout rates. Recently, Rödström et al (2020) have been able to solve the structure of human TASK-1 by X-ray crystallography. They could show that high-affinity inhibitors are trapped in a vestibule below the selectivity filter by an X-gate, leading to the above mentioned low washout rates (Rödström et al, 2020).…”

“…Recently, Rödström et al (2020) have been able to solve the structure of human TASK-1 by X-ray crystallography. They could show that high-affinity inhibitors are trapped in a vestibule below the selectivity filter by an X-gate, leading to the above mentioned low washout rates (Rödström et al, 2020). The entrapment has to be considered when interpreting data from pharmacokinetic-pharmacodynamic studies as inhibitors will remain bound and active for a longer time than predicted by these studies.…”

Norfluoxetine inhibits TREK-2 K2P channels by multiple mechanisms including state-independent effects on the selectivity filter gate

“…It has recently been shown that some K2P channels possess a lower gate analogous to the classical helix bundle crossing found in many other types of K + channels (Li et al, 2020;Rodstrom et al, 2020). However, most K2P channels, including TREK channels, do not have a lower gate (Brohawn et al, 2012;Miller and Long, 2012;Lolicato et al, 2014;Dong et al, 2015;Lolicato et al, 2017).…”

Multiple Mechanisms Underlie State-Independent Inhibitory Effects of Norfluoxetine on TREK-2 K2P Channels

“…It has recently been shown that some K2P channels possess a lower gate analogous to the classical helix bundle-crossing found in many other types of K + channels (Li et al, 2020;Rödstrom et al, 2020). However, most K2P channels, including TREK channels, do not have a lower gate (Brohawn et al, 2012;Miller and Long, 2012;Lolicato et al, 2014;Dong et al, 2015).…”