Computational modelling of specific serotonin reuptake inhibitor inhibition on the TREK-2 channel

The TREK-2 is a mechanosensitive potassium channel in the two-pore (K2P) potassium channel subfamily. Recent studies of the TREK-2 channel with norfluoxetine reveal that norfluoxetine stabilises a conformation with a lower open probability and disrupts channel gating through a selectivity filter. In addition, multiple specific serotonin reuptake inhibitors (SSRIs) have previously been shown to inhibit the TREK channels subfamily. However, the mechanism of lipid-like SSRI inhibition to the TREK-2 channel is currently unclear. Using molecular dynamic simulation, we show that fluoxetine and escitalopram share the same binding pocket on the TREK-2 channel. We show that fluoxetine inhibits the TREK-2 channel using POPC lipid and directly disrupts the channel gating at the selectivity filter, while escitalopram is a traditional pore blocker, which also disrupts the selectivity filter gating but without POPC dependent inhibition. In addition, we show that both fluoxetine and escitalopram prevent a down-to-up transition when the pressure is applied to the system, showing a conserved mechanism of TREK-2 inhibition. Together, our work reveals mechanistic insight into TREK-2 channel inhibition by lipid-like antidepressants, which could further shed light on rational drug design in the future.