A selective G betagamma-linked intracellular mechanism for modulation of a ligand-gated ion channel by ethanol.
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 betagamma 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 betagamma 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.
Yevenes
Gonzalo E
GE
Laboratory of Neurophysiology, Department of Physiology, University of Concepción, P. O. Box 160-C, Concepcion, Chile.
Moraga-Cid
Gustavo
G
Peoples
Robert W
RW
Schmalzing
Günther
G
Aguayo
Luis G
LG
D000431:Ethanol / Q000494:pharmacology*; D044387:GTP-Binding Protein beta Subunits / Q000502:physiology*; D044388:GTP-Binding Protein gamma Subunits / Q000502:physiology*; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D007473:Ion Channels / Q000187:drug effects*; D008024:Ligands; D018009:Receptors, Glycine / Q000819:agonists
D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D007473:Ion Channels; D008024:Ligands; D018009:Receptors, Glycine; D000431:Ethanol