A selective G beta gamma-linked intracellular mechanism for modulation of a ligand-gated ion channel by ethanol

Yevenes, GE; Moraga-Cid, G; Peoples, RW; Schmalzing, G; Aguayo, LG

Abstract

The current understanding about ethanol effects on the ligand-gated ion channel (LGIC) superfamily has been restricted to identify potential binding sites within transmembrane (TM) domains in the Cys-loop family. Here, we demonstrate a key role of the TM3-4 intracellular loop and Gβγ signaling for potentiation of glycine receptors (GlyRs) by ethanol. We discovered 2 motifs within the large intracellular loop of the GlyR α1 subunit that are critical for the actions of pharmacological concentrations of ethanol. Significantly, the sites were ethanol-specific because they did not alter the sensitivity to general anesthetics, neurosteroids, or longer n-alcohols. Furthermore, Gβγ scavengers selectively attenuated the ethanol effects on recombinant and native neuronal GlyRs. These results show a selective mechanism for low-ethanol concentration effects on the GlyR and provide a mechanism on ethanol pharmacology, which may be applicable to other LGIC members. Moreover, these data provide an opportunity to develop new genetically modified animal models and novel drugs to treat alcohol-related medical concerns. © 2008 by The National Academy of Sciences of the USA.

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Título según WOS: A selective G beta gamma-linked intracellular mechanism for modulation of a ligand-gated ion channel by ethanol
Título según SCOPUS: A selective Gß?-linked intracellular mechanism for modulation of a ligand-gated ion channel by ethanol
Título de la Revista: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volumen: 105
Número: 51
Editorial: NATL ACAD SCIENCES
Fecha de publicación: 2008
Página de inicio: 20523
Página final: 20528
Idioma: English
URL: http://www.pnas.org/cgi/doi/10.1073/pnas.0806257105
DOI:

10.1073/pnas.0806257105

Notas: ISI, SCOPUS