title: Structural models of ligand-gated ion channels: sites of action for anesthetics and ethanol.
abstract: The molecular mechanism(s) of action of anesthetic, and especially, intoxicating doses of alcohol (ethanol [EtOH]) have been of interest even before the advent of the Research Society on Alcoholism. Recent physiological, genetic, and biochemical studies have pin-pointed molecular targets for anesthetics and EtOH in the brain as ligand-gated ion channel (LGIC) membrane proteins, especially the pentameric (5 subunit) Cys-loop superfamily of neurotransmitter receptors including nicotinic acetylcholine (nAChRs), GABAA (GABAA Rs), and glycine receptors (GlyRs). The ability to demonstrate molecular and structural elements of these proteins critical for the behavioral effects of these drugs on animals and humans provides convincing evidence for their role in the drugs' actions. Amino acid residues necessary for pharmacologically relevant allosteric modulation of LGIC function by anesthetics and EtOH have been identified in these channel proteins. Site-directed mutagenesis revealed potential allosteric modulatory sites in both the trans-membrane domain (TMD) and extracellular domain (ECD). Potential sites of action and binding have been deduced from homology modeling of other LGICs with structures known from crystallography and cryo-electron microscopy studies. Direct information about ligand binding in the TMD has been obtained by photoaffinity labeling, especially in GABAA Rs. Recent structural information from crystallized procaryotic (ELIC and GLIC) and eukaryotic (GluCl) LGICs allows refinement of the structural models including evaluation of possible sites of EtOH action.
authors.affiliation: Department of Molecular & Medical Pharmacology , David Geffen School of Medicine at UCLA, Los Angeles, California; Department of Anesthesiology , David Geffen School of Medicine at UCLA, Los Angeles, California.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Olsen
authors.forename: Guo-Dong
authors.initials: GD
authors.lastname: Li
authors.forename: Martin
authors.initials: M
authors.lastname: Wallner
authors.forename: James R
authors.initials: JR
authors.lastname: Trudell
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Bertaccini
authors.forename: Erik
authors.initials: E
authors.lastname: Lindahl
authors.forename: Keith W
authors.initials: KW
authors.lastname: Miller
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Alkana
authors.forename: Daryl L
authors.initials: DL
authors.lastname: Davies
mesh_terms: D000595:Amino Acid Sequence; D000777:Anesthetics / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002492:Central Nervous System Depressants / Q000378:metabolism / Q000494:pharmacology*; D058466:Cysteine Loop Ligand-Gated Ion Channel Receptors / Q000187:drug effects* / Q000378:metabolism; D000431:Ethanol / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D015394:Molecular Structure
chemical_list: D000777:Anesthetics; D002492:Central Nervous System Depressants; D058466:Cysteine Loop Ligand-Gated Ion Channel Receptors; D000431:Ethanol
keywords: ELIC; Ethanol Sites of Action; GABAA Receptors; GLIC; GluCl Pentameric Ion Channels; Loop 2