Glycine and γ-aminobutyric acid (GABA)A receptors belong to the “superfamily” of ion channels and are sensitive to allosteric modulation by alcohols such as ethanol and butanol. We have recently shown that mutation of Ser-267 to Ile in the α1 subunit abolishes ethanol regulation of glycine receptors (Gly-R).
In the present study, we examined a pair of chimeric receptors in which a 45-amino acid domain encompassing transmembrane domains 2 and 3 was exchanged between the Gly-Rα1 and γ-aminobutyric acid ρ1 subunits. Detailed pharmacological analysis of these chimeras confirmed that this domain of Gly-R causes enhancement of receptor function by ethanol and butanol.
A comprehensive series of mutations at Ser-267 in the Gly-Rα1 subunit was also prepared, and the resulting homomeric receptors were expressed and tested for sensitivity to glycine and allosteric modulation by alcohols. All mutant receptors were successfully expressed in Xenopus oocytes.
Mutation of Ser-267 to small amino acid residues such as Gly or Ala generated receptors in which glycine reactions were potentiated by ethanol. As we reported previously, the Gly-Rα1 mutant (Ser-267 → Ile) was completely insensitive to ethanol; mutation of Ser-267 to Val had a similar effect. Mutation of Ser-267 to large residues such as His, Cys, or Tyr resulted in inhibition of Gly-R function by ethanol.
These results indicate that the size of the amino acid residue at the α267 position plays a critical role in determining the functional consequences of allosteric modulation of Gly-R by alcohols.
MEMBRANES AND BIOENERGETICS: Enhancement of Glycine Receptor Function by Ethanol Is Inversely Correlated with Molecular Volume at Position α267
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