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Publication Abstract from PubMed

The sodium-activated Slo2.2 channel is abundantly expressed in the brain, playing a critical role in regulating neuronal excitability. The Na(+)-binding site and the underlying mechanisms of Na(+)-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 A, 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(+) and Zn(2+) sites, which stabilize the channel in the closed conformation. The open Slo2.2 structure reveals at least two Na(+)-sensitive sites where Na(+) 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(+) sensation, and inhibition.

Structural basis of human Slo2.2 channel gating and modulation.,Zhang J, Liu S, Fan J, Yan R, Huang B, Zhou F, Yuan T, Gong J, Huang Z, Jiang D Cell Rep. 2023 Jul 25;42(8):112858. doi: 10.1016/j.celrep.2023.112858. PMID:37494189^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.