title: Unique general anesthetic binding sites within distinct conformational states of the nicotinic acetylcholine receptor.
abstract: General anesthesia is a complex behavioral state provoked by the pharmacological action of a broad range of structurally different hydrophobic molecules called general anesthetics (GAs) on receptor members of the genetically linked ligand-gated ion channel (LGIC) superfamily. This superfamily includes nicotinic acetylcholine (AChRs), type A and C gamma-aminobutyric acid (GABAAR and GABACR), glycine (GlyR), and type 3 5-hydroxytryptamine (5-HT3R) receptors. This review focuses on recent advances in the localization of GA binding sites on conformationally and compositionally distinct AChRs. The experimental evidence outlined in this review suggests that: 1. Several neuronal-type AChRs might be targets for the pharmacological action of distinct GAs. 2. The molecular components of a specific GA binding site on a certain receptor subtype are different from the structural determinants of the locus for the same GA on a different receptor subtype. 3. There are unique binding sites for distinct GAs in the same receptor protein. 4. A GA can activate, potentiate, or inhibit an ion channel, indicating the existence of more than one binding site for the same GA. 5. The affinity of a specific GA depends on the conformational state of the receptor. 6. GAs inhibition channels by at least two mechanisms, an open-channel-blocking and/or an allosteric mechanism. 7. Certain GAs may inhibit AChR function by competing for the agonist binding sites or by augmenting the desensitization rate.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, California 91766, USA.
authors.forename: Hugo R
authors.initials: HR
authors.lastname: Arias
authors.forename: William R
authors.initials: WR
authors.lastname: Kem
authors.forename: James R
authors.initials: JR
authors.lastname: Trudell
authors.forename: Michael P
authors.initials: MP
authors.lastname: Blanton
mesh_terms: D018681:Anesthetics, General / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D006801:Humans; D007473:Ion Channels / Q000493:pharmacokinetics*; D008968:Molecular Conformation; D021122:Protein Subunits / Q000737:chemistry; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000502:physiology*; D013256:Steroids / Q000493:pharmacokinetics
chemical_list: D018681:Anesthetics, General; D007473:Ion Channels; D021122:Protein Subunits; D011978:Receptors, Nicotinic; D013256:Steroids