Molecular requirements for ethanol differential allosteric modulation of glycine receptors based on selective Gbetagamma modulation.

The Journal of Biological Chemistry
Gonzalo E YevenesLuis G Aguayo

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 ligand-gated ion receptor members, the GlyR adult α(1) and embryonic α(2) subunits, can be modified through selective mutations that rescued or impaired Gβγ modulation. Even though both isoforms were able to physically interact with Gβγ, only the α(1) GlyR was functionally modulated by Gβγ and pharmacological ethanol concentrations. Remarkably, the simultaneous switching of two transmembrane and a single extracellular residue in α(2) GlyRs was enough to generate GlyRs modulated by Gβγ and low ethanol concentrations. Interestingly, although 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 sen...Continue Reading

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Citations

Jan 15, 2013·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Kimberly A BadanichJohn J Woodward
Aug 9, 2011·The Journal of Pharmacology and Experimental Therapeutics·Gonzalo E YévenesLuis G Aguayo
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Sep 9, 2011·PloS One·Gonzalo E Yévenes, Hanns Ulrich Zeilhofer
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May 12, 2011·British Journal of Pharmacology·Gonzalo E Yevenes, Hanns Ulrich Zeilhofer
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Oct 24, 2014·The Journal of Pharmacology and Experimental Therapeutics·Carlos F BurgosLuis G Aguayo
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Jun 8, 2017·Frontiers in Molecular Neuroscience·Yan ZhangAngelo Keramidas
May 22, 2020·British Journal of Pharmacology·Loreto San MartinLuis G Aguayo
Nov 9, 2021·Frontiers in Molecular Neuroscience·Loreto S San MartinLuis G Aguayo

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