title: Molecular properties important for inhaled anesthetic action on human 5-HT3A receptors.
abstract: Although inhaled anesthetics have diverse effects on 5-hydroxytryptamine type 3 (5-HT3A) receptors, the mechanism accounting for this diversity is not understood. Studies have shown that modulation of 5-HT3A receptor currents by n-alcohols depends on molecular volume, suggesting that steric interactions between n-alcohols and their binding sites define their action on this receptor. Electrostatic interactions also play an important role in anesthetic action on other ligand-gated receptors. We aimed to determine the contribution of molecular volume and electrostatics in defining volatile anesthetic actions on 5-HT3A receptors. Human 5-HT3A receptors were expressed in, and recorded from, Xenopus oocytes using the two-electrode voltage-clamp technique. The effects of a range of volatile anesthetics, n-alcohols, and nonhalogenated alkanes on submaximal serotonin-evoked peak currents, and full serotonin concentration-response curves were defined. Volatile anesthetics and n-alcohols, but not alkanes, smaller than 0.120 nm3 enhanced submaximal serotonin-evoked peak currents whereas all larger agents reduced currents. Most compounds tested inhibited maximal serotonin-evoked peak currents to varying degrees. However, only agents smaller than 0.120 nm3 shifted the 5-HT3A receptor's serotonin concentration-response curve to the left, whereas larger anesthetics shifted them to the right. Modulation of human 5-HT3A-mediated currents by volatile anesthetics exhibits a dependence on molecular volume consistent with the n-alcohols, suggesting that both classes of agents may enhance 5-HT3A receptor function via the same mechanism. Furthermore, the enhancing but not inhibiting effects of anesthetic compounds on 5-HT3A receptor currents are modulated by electrostatic interactions.
authors.affiliation: Department of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Renna J N
authors.initials: RJN
authors.lastname: Stevens
authors.forename: Dirk
authors.initials: D
authors.lastname: Rüsch
authors.forename: Paul A
authors.initials: PA
authors.lastname: Davies
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Raines
mesh_terms: D000280:Administration, Inhalation; D000438:Alcohols / Q000494:pharmacology; D000465:Algorithms; D018685:Anesthetics, Inhalation / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D009865:Oocytes / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3 / Q000737:chemistry* / Q000187:drug effects* / Q000235:genetics; D012701:Serotonin / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: D000438:Alcohols; D018685:Anesthetics, Inhalation; D018076:DNA, Complementary; D044406:Receptors, Serotonin, 5-HT3; D012701:Serotonin