K2P channel gating mechanisms revealed by structures of TREK-2 and a complex with Prozac

摘要

TREK-2 (KCNK10/K2P10), a two-pore domain (K2P) potassium channel, is gated by polymodal stimuli such as stretch, fatty acids and pH, and by several drugs including the antidepressant fluoxetine (Prozac) and its metabolite norfluoxetine. However, the mechanisms that control channel gating are unclear. Here we present crystal structures of the human TREK-2 channel in two conformations and in complex with norfluoxetine, a state-dependent blocker. Norfluoxetine binds within intramembrane fenestrations found only in one of these two conformations, and channel activation by arachidonic acid and mechanical stretch involves conversion between these states via movement of the pore-lining helices. These results therefore not only provide a structural explanation for TREK channel mechanosensitivity, but also their regulation by other diverse stimuli and explain how Prozac inhibits TREK channels.