A Non-canonical Voltage-Sensing Mechanism Controls Gating in K2P K+ Channels

Abstract

SummaryTwo-pore domain (K2P) K+ channels are major regulators of excitability that endow cells with an outwardly rectifying background “leak” conductance. In some K2P channels, strong voltage-dependent activation has been observed, but the mechanism remains unresolved because they lack a canonical voltage-sensing domain. Here, we show voltage-dependent gating is common to most K2P channels and that this voltage sensitivity originates from the movement of three to four ions into the high electric field of an inactive selectivity filter. Overall, this ion-flux gating mechanism generates a one-way “check valve” within the filter because outward movement of K+ induces filter opening, whereas inward movement promotes inactivation. Furthermore, many physiological stimuli switch off this flux gating mode to convert K2P channels into a leak conductance. These findings provide insight into the functional plasticity of a K+-selective filter and also refine our understanding of K2P channels and the mechanisms by which ion channels can sense voltage.

Selective Small Molecule Activators of TREK-2 Channels Stimulate Dorsal Root Ganglion c-Fiber Nociceptor Two-Pore-Domain Potassium Channel Currents and Limit Calcium Influx

“…Some of the TREK-2 activators caused inhibition of TREK-1 channels, and these molecules will provide structural insights into what controls TREK channel biophysical activity and outward rectification. 34 For example, T2A3 activates TREK-2 and at higher concentrations slightly inhibits TREK-1 as well as causing less TREK-2 outward rectification. As TREK-2 rectification is also reduced by a number of other activators such as arachidonic acid, T2A3 may activate TREK-2 channels like these activators and differentially from T2A8 or T2A9 that only modestly influence rectification.…”

Gating, Regulation, and Structure in K2P K+ Channels: In Varietate Concordia?

“…Ashmole et al (2009) hypothesized the existence of an inner helices bundle crossing activation gate to explain voltage gating of TASK-3). The effect of voltage is quite weak, and the measured gating charge is 0.17, which is small compared with ∼2 for the ensemble of K 2P channels studied by Schewe et al (2016). Nevertheless, this can be enhanced by mutations affecting pore lining in helices TM2 and TM4 and virtually abolished by mutating the putative glycine hinge residues to alanine residues.…”

“…Gating in response to voltage does occur in K 2P channels, although it has been largely ignored and remained poorly understood (Renigunta et al, 2015); however, recent detailed work (Schewe et al, 2016) provides a robust hypothesis of how the voltage-dependence of K 2P channels might work in the absence of a conventional voltage-sensor. It was shown that voltage dependence was present in most K 2P channels, except for TWIK-1, and relies crucially on the movement of the permeant ion and therefore on its electrochemical potential difference.…”

“…To what extent and for which K 2P channels the voltage dependence plays a physiologic role is not known, particularly since voltagedependence appears to be rather unimportant in channels activated by other pathways. The model presented by Schewe et al (2016) will prompt further work to explore this point, perhaps using channels in their native environment. Ashmole et al (2009) hypothesized the existence of an inner helices bundle crossing activation gate to explain voltage gating of TASK-3).…”

Nonequilibrium Thermodynamics of Ion Flux through Membrane Channels

“…In K2P K + channels, the permeation barrier is greatly affected by the direction of the K + flux driven by the electrochemical gradient. A model of flux-coupled gating in the multi-ion selectivity filter in the K2P K + channel has been proposed to explain the intrinsic strongly outward rectifying current-voltage relationship without extracellular or intracellular blockers [35]. The gating barrier to ion permeation within the channel pore is "driving force"-dependent because the barrier is significantly affected by the direction of the K + ion flux.…”