Document Type
Article
Language
eng
Format of Original
11 p.
Publication Date
9-2010
Publisher
American Society for Biochemistry and Molecular Biology
Source Publication
Journal of Biological Chemistry
Source ISSN
0021-9258
Original Item ID
DOI: 10.1074/jbc.M110.134676
Abstract
It is now believed that the allosteric modulation produced by ethanol in glycine receptors (GlyRs) depends on alcohol binding to discrete sites within the protein structure. Thus, the differential ethanol sensitivity of diverse GlyR isoforms and mutants was explained by the presence of specific residues in putative alcohol pockets. Here, we demonstrate that ethanol sensitivity in two LGIC members, the GlyR adult α1 and embryonic α2 subunits, can be modified through selective mutations that rescued or impaired Gβγ modulation. Even though that both isoforms were able to physically interact with Gβγ, only the α1 GlyR was functionally modulated by Gβγ and pharmacological ethanol concentrations. Remarkably, the simultaneous switching of two transmembrane and a single extracellular residue in α2 GlyRs was enough to generate GlyRs modulated by Gβγ and low ethanol concentrations. Interestingly, while we found that these TM residues were different to those in the alcohol binding site, the extracellular residue was recently implicated in conformational changes important to generate a pre-open activated state that precedes ion channel gating. Thus, these results support the idea that the differential ethanol sensitivity of these two GlyR isoforms rests on conformational changes in transmembrane and extracellular residues within the ion channel structure rather than in differences in alcohol binding pockets. Our results describe the molecular basis for the differential ethanol sensitivity of two ligand-gated ion receptor members based on selective Gβγ modulation and provide a new mechanistic framework for allosteric modulations of abuse drugs.
Recommended Citation
Yevenes, Gonzalo E.; Moraga-Cid, Gustavo; Avila, Ariel; Guzman, Leonardo; Figueroa, Maximiliano; Peoples, Robert W.; and Aguayo, Luis G., "Molecular Requirements for Ethanol Differential Allosteric Modulation of Ligand-Gated Ion Channels Based on Selective Gβγ Modulation" (2010). Biomedical Sciences Faculty Research and Publications. 38.
https://epublications.marquette.edu/biomedsci_fac/38
Comments
Accepted version. Journal of Biological Chemistry, Vol. 285, No. 39 (September 2010): 30203-30213. DOI. © 2010 American Society for Biochemistry and Molecular Biology. Used with permission.