Insights into Selectivity Filter Gating of K2P Channels from Single-Channel Recordings

Abstract

Polymodal K2P channels are regulated by stimuli such as voltage, membrane tension, pH and diverse signalling events. TREK subfamily K2P channels, like some other K+ channels e.g. BK channels, have been shown to gate primarily at the selectivity filter (SF). The TREK-2 single-channel conductance of 200-300 pS makes it accessible to study SF gating at high resolution with exceptional signal to noise ratio. The TREK subfamily in particular is a target for drug discovery because of its involvement in pain perception. Activators of these channels are therefore promising analgesics, through their potential to dampen cellular excitability. Here, we show that applying the K2P channel activator BL1249, in addition to affecting open-probability, increases the apparent single-channel conductance of TREK-2 and we have investigated the various mechanisms which may account for these changes in both conductance and gating. Such studies not only expand our knowledge of the principal mechanisms underlying SF gating of K+ channels but may also help aid our understanding of how some K+ channel agonists exert their effects on the selectivity filter.