Structural Models of Ligand-Gated Ion Channels: Sites of Action for Anesthetics and Ethanol

• Published in: Alcoholism, clinical and experimental research Vol. 38; no. 3; pp. 595 - 603
• Main Authors: Olsen, Richard W., Li, Guo-Dong, Wallner, Martin, Trudell, James R., Bertaccini, Edward J., Lindahl, Erik, Miller, Keith W., Alkana, Ronald L., Davies, Daryl L.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.03.2014; Wiley Subscription Services, Inc
• Subjects: Amino Acid Sequence; Anesthetics - metabolism; Anesthetics - pharmacology; Animals; Central Nervous System Depressants - metabolism; Central Nervous System Depressants - pharmacology; Cysteine Loop Ligand-Gated Ion Channel Receptors - drug effects; Cysteine Loop Ligand-Gated Ion Channel Receptors - metabolism; ELIC; Ethanol - metabolism; Ethanol - pharmacology; Ethanol Sites of Action; GABA(A) Receptors; GABAA Receptors; GLIC; GluCl Pentameric Ion Channels; Humans; Ligands; Loop 2; Models, Molecular; Molecular Dynamics Simulation; Molecular Sequence Data; Molecular Structure; Proteins; ELIC; GluCl Pentameric Ion Channels; Ethanol Sites of Action; GABAA Receptors; Loop 2; GLIC
• ISSN: 0145-6008; 1530-0277; 1530-0277
• DOI: 10.1111/acer.12283

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 (GABAARs), 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 GABAARs. 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.