Direct interactions of anesthetics and nonanesthetics with the nicotinic acetylcholine receptor pore.

(1) We review evidence that anesthetics inhibit peripheral nAChR cation translocation by binding directly to a protein site in the transmembrane pore. (2) This site is near the middle of the pore-forming M2 domains on alpha and beta subunits, but further from the homologous portions of gamma and delta subunits. (3) Interactions between both anesthetics and nonanesthetics with the nAChR pore site are determined primarily by hydrophobic forces rather than steric factors. (4) Anesthetics and nonanesthetics display different state-dependent accessibility to this site, suggesting a mechanism for the different in vivo actions of these two classes of drugs.