Fig. 1: Etomidate stabilizes a desensitized state through TMD binding.

a Simplified gating cycle cartoon for the nicotinic receptor. Acetylcholine (ACh) binding shifts the conformational equilibrium toward a conducting, activated state, then to the more stable nonconducting desensitized state. b Two-electrode voltage clamp (TEVC) electrophysiology shows activation by acetylcholine and dose-dependent receptor antagonism by etomidate (Eto). R, A, and D indicate channel resting state, and activation and presumed desensitization components of current response. Red triangles highlight etomidate increasing apparent desensitization rate. Incomplete recovery in final acetylcholine application is from slow washout of etomidate, consistent with its membrane partitioning. Similar responses were seen from n = 8 independent cells. c Side view of the overall cryo-EM map of the receptor-etomidate-choline complex; α subunit is in green, β subunit in khaki, γ subunit in blue, δ subunit in violet, choline in red, etomidate in gold, cholesterols in tomato red, and phospholipids in pink; the lipid nanodisc is shown as a semitransparent surface. α_γ and α_δ subunits are named based on their neighboring complementary subunits. d Side view of two α subunits showing permeation pathway as dots representing solvent-accessible surface colored by diameter; purple is 2.8–5.6 Å diameter, while diameter > 5.6 Å is shown in blue. Thr2ʹ that forms the pore constriction is shown as sticks. e Etomidate-receptor interactions in α_γ subunit are shown as sticks with corresponding density. f Choline at α/γ interface.