Potassium channel subfamily T member 1
intracellular sodium-activated potassium channel activity
Structural basis of human Slo2.2 channel gating and modulation.
The sodium-activated Slo2.2 channel is abundantly expressed in the brain, playing a critical role in regulating neuronal excitability. The Na<sup>+</sup>-binding site and the underlying mechanisms of Na<sup>+</sup>-dependent activation remain unclear. Here, we present cryoelectron microscopy (cryo-EM) structures of human Slo2.2 in closed, open, and inhibitor-bound form at resolutions of 2.6-3.2 Å, revealing gating mechanisms of Slo2.2 regulation by cations and a potent inhibitor. The cytoplasmic gating ring domain of the closed Slo2.2 harbors multiple K<sup>+</sup> and Zn<sup>2+</sup> sites, which stabilize the channel in the closed conformation. The open Slo2.2 structure reveals at least two Na<sup>+</sup>-sensitive sites where Na<sup>+</sup> binding induces expansion and rotation of the gating ring that opens the inner gate. Furthermore, a potent inhibitor wedges into a pocket formed by pore helix and S6 helix and blocks the pore. Together, our results provide a comprehensive structural framework for the investigation of Slo2.2 channel gating, Na<sup>+</sup> sensation, and inhibition.