Reversal of ethanol-induced intoxication by a novel modulator of Gβγ protein potentiation of the glycine receptor

Loreto San Martin, Fabian Cerda, Chunyang Jin, Veronica Jimenez, Gonzalo E. Yevenes, Tania Hernandez, Daniela Nova, Jorge Fuentealba, Luis G. Aguayo, Leonardo Guzman

Resultado de la investigación: Article

4 Citas (Scopus)

Resumen

The acute intoxicating effects of ethanol in the central nervous system result from the modulation of several molecular targets. It is widely accepted that ethanol enhances the activity of the glycine receptor (GlyR), thus enhancing inhibitory neurotransmission, leading to motor effects, sedation, and respiratory depression. We previously reported that small peptides interfered with the binding of Gβγ to the GlyR and consequently inhibited the ethanol-induced potentiation of the receptor. Now, using virtual screening, we identified a subset of small molecules capable of interacting with the binding site of Gβγ. One of these compounds, M554, inhibited the ethanol potentiation of the GlyR in both evoked currents and synaptic transmission in vitro. When this compound was tested in vivo in mice treated with ethanol (1-3.5 g/kg), it was found to induce a faster recovery of motor incoordination in rotarod experiments and a shorter sedative effect in loss of righting reflex assays. This study describes a novel molecule that might be relevant for the design of useful therapeutic compounds in the treatment of acute alcohol intoxication.

Idioma originalEnglish
Páginas (desde-hasta)18791-18798
Número de páginas8
PublicaciónJournal of Biological Chemistry
Volumen291
N.º36
DOI
EstadoPublished - 2 sep 2016

Huella dactilar

Glycine Receptors
GTP-Binding Proteins
Modulators
Ethanol
Synaptic Transmission
Righting Reflex
Alcoholic Intoxication
Molecules
Neurology
Ataxia
Hypnotics and Sedatives
Respiratory Insufficiency
Assays
Screening
Central Nervous System
Binding Sites
Alcohols
Modulation
Recovery
Peptides

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Citar esto

Martin, Loreto San ; Cerda, Fabian ; Jin, Chunyang ; Jimenez, Veronica ; Yevenes, Gonzalo E. ; Hernandez, Tania ; Nova, Daniela ; Fuentealba, Jorge ; Aguayo, Luis G. ; Guzman, Leonardo. / Reversal of ethanol-induced intoxication by a novel modulator of Gβγ protein potentiation of the glycine receptor. En: Journal of Biological Chemistry. 2016 ; Vol. 291, N.º 36. pp. 18791-18798.
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abstract = "The acute intoxicating effects of ethanol in the central nervous system result from the modulation of several molecular targets. It is widely accepted that ethanol enhances the activity of the glycine receptor (GlyR), thus enhancing inhibitory neurotransmission, leading to motor effects, sedation, and respiratory depression. We previously reported that small peptides interfered with the binding of Gβγ to the GlyR and consequently inhibited the ethanol-induced potentiation of the receptor. Now, using virtual screening, we identified a subset of small molecules capable of interacting with the binding site of Gβγ. One of these compounds, M554, inhibited the ethanol potentiation of the GlyR in both evoked currents and synaptic transmission in vitro. When this compound was tested in vivo in mice treated with ethanol (1-3.5 g/kg), it was found to induce a faster recovery of motor incoordination in rotarod experiments and a shorter sedative effect in loss of righting reflex assays. This study describes a novel molecule that might be relevant for the design of useful therapeutic compounds in the treatment of acute alcohol intoxication.",
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Martin, LS, Cerda, F, Jin, C, Jimenez, V, Yevenes, GE, Hernandez, T, Nova, D, Fuentealba, J, Aguayo, LG & Guzman, L 2016, 'Reversal of ethanol-induced intoxication by a novel modulator of Gβγ protein potentiation of the glycine receptor', Journal of Biological Chemistry, vol. 291, n.º 36, pp. 18791-18798. https://doi.org/10.1074/jbc.M116.740555

Reversal of ethanol-induced intoxication by a novel modulator of Gβγ protein potentiation of the glycine receptor. / Martin, Loreto San; Cerda, Fabian; Jin, Chunyang; Jimenez, Veronica; Yevenes, Gonzalo E.; Hernandez, Tania; Nova, Daniela; Fuentealba, Jorge; Aguayo, Luis G.; Guzman, Leonardo.

En: Journal of Biological Chemistry, Vol. 291, N.º 36, 02.09.2016, p. 18791-18798.

Resultado de la investigación: Article

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T1 - Reversal of ethanol-induced intoxication by a novel modulator of Gβγ protein potentiation of the glycine receptor

AU - Martin, Loreto San

AU - Cerda, Fabian

AU - Jin, Chunyang

AU - Jimenez, Veronica

AU - Yevenes, Gonzalo E.

AU - Hernandez, Tania

AU - Nova, Daniela

AU - Fuentealba, Jorge

AU - Aguayo, Luis G.

AU - Guzman, Leonardo

PY - 2016/9/2

Y1 - 2016/9/2

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