Structural Models of Ligand‐Gated Ion Channels: Sites of Action for Anesthetics and Ethanol
Copyright policy )Structural Models of Ligand‐Gated Ion Channels: Sites of Action for Anesthetics and Ethanol
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 theResearchSociety onAlcoholism. Recent physiological, genetic, and biochemical studies have pin‐pointed molecular targets for anesthetics andEtOHin 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 ofLGICfunction by anesthetics andEtOHhave 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 otherLGICs with structures known from crystallography and cryo‐electron microscopy studies. Direct information about ligand binding in theTMDhas been obtained by photoaffinity labeling, especially inGABAARs. Recent structural information from crystallized procaryotic (ELICandGLIC) and eukaryotic (GluCl)LGICs allows refinement of the structural models including evaluation of possible sites ofEtOHaction.
- Royal Institute of Technology Sweden
- Massachusetts General Hospital United States
- University of Chicago United States
- David Geffen School of Medicine at UCLA United States
- University of California, Los Angeles United States
Models, Molecular, Ethanol, Molecular Structure, Molecular Sequence Data, Central Nervous System Depressants, Molecular Dynamics Simulation, Animals, Humans, Amino Acid Sequence, Cysteine Loop Ligand-Gated Ion Channel Receptors, Anesthetics
Models, Molecular, Ethanol, Molecular Structure, Molecular Sequence Data, Central Nervous System Depressants, Molecular Dynamics Simulation, Animals, Humans, Amino Acid Sequence, Cysteine Loop Ligand-Gated Ion Channel Receptors, Anesthetics
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