Inhibition of the ethanol-induced potentiation of ?1 glycine receptor by a small peptide that interferes with G?? binding.

ABSTRACT: G?? interaction with GlyR is an important determinant in ethanol potentiation of this channel.A small peptide, RQH(C7), can inhibit ethanol potentiation of GlyR currents.Results with RQH(C7) indicate that ethanol mediated potentiation of GlyR is in part by G?? activation.Molecular interaction between G?? and GlyR could be used as a target for pharmacological modification of ethanol effects. Previous studies indicate that ethanol can modulate glycine receptors (GlyR), in part, through G?? interaction with basic residues in the intracellular loop. In this study, we show that a seven-amino acid peptide (RQH(C7)), which has the primary structure of a motif in the large intracellular loop of GlyR (GlyR-IL), was able to inhibit the ethanol-elicited potentiation of this channel from 47 ± 2 to 16 ± 4%, without interfering with the effect of G?? on GIRK (G protein activated inwardly rectifying potassium channel) activation. RQH(C7) displayed a concentration-dependent effect on ethanol action in evoked and synaptic currents. A fragment of GlyR-IL without the basic amino acids did not interact with G?? or inhibit ethanol potentiation of GlyR. In silico analysis using docking and molecular dynamics allowed to identify a region of ~350Å(2) involving aspartic acids 186, 228, and 246 in G?? where we propose that RQH(C7) binds and exerts its blocking action on the effect of ethanol in GlyR.

SUBMITTER: San Martin L 

PROVIDER: S-EPMC3504784 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature