期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 105, 期 51, 页码 20523-20528出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0806257105
关键词
pharmacology; signal transduction; glycine receptor; alcoholism; G proteins
资金
- National Institute on Alcohol Abuse and Alcoholism (National Institutes of Health) [R01 AA15150]
- Fondo Nacional de Desarrollo Cientfico y Tecnologico [1060368]
- Comision Nacional de Investigacion Cientifica y Tecnologica [AT-4040102]
- Deutsche Forschungsgemeinschaft [Schm536/4-I]
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 G beta gamma signaling for potentiation of glycine receptors (GlyRs) by ethanol. We discovered 2 motifs within the large intracellular loop of the GlyR alpha(1) 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, G beta gamma 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.
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