One pocket to activate them all: Efforts on understanding the modulator pocket in K2P channels

The modulator pocket is a cryptic site discovered in the TREK1 K2P channel that accommodates agonists capable of increasing the channel's activity. Since its discovery, equivalent sites in other K2P channels have been shown to bind various ligands, both endogenous and exogenous. In this review, we attempt to elucidate how the modulator pocket contributes to K2P channel activation. To this end, we first describe the gating mechanisms reported in the literature and rationalize their modes of action. We then highlight previous experimental and computational evidence for agonists that bind to the modulator pocket, together with mutations at this site that affect gating. Finally, we elaborate how the activation signal arising from the modulator pocket is transduced to the gates in K2P channels. In doing so, we outline a potential common modulator pocket architecture across K2P channels: a largely amphipathic structure -consistent with the expected properties of a pocket exposed at the interface between a hydrophobic membrane and the aqueous solvent- but still with some important channel-sequence-variations. This architecture and its key differences can be leveraged for the design of new selective and potent modulators.