A novel domain of the inhibitory glycine receptor determining antagonist efficacies: further evidence for partial agonism resulting from self-inhibition.

Different amino side chains in the N-terminal extracellular region of the inhibitory glycine receptor (GlyR) have been shown to be crucial for ligand recognition. Here we describe a novel domain of the GlyRalpha1 subunit that constitutes an important determinant of antagonist activity. The antagonists strychnine, nipecotic acid, and isobutyric acid displayed reduced potencies at recombinant GlyRs formed from alpha1 subunits, in which lysine 104, phenylalanine 108, or threonine 112 were replaced by alanine. Agonist affinities, in contrast, were slightly increased at these mutant receptors. Taurine and beta-aminoisobutyric acid, which are partial agonists at the wild-type GlyR, behaved as full agonists at the mutant GlyRs and failed to inhibit glycine-induced currents. This is consistent with apolar residues at positions 104, 108, and 112 of the alpha1 subunit reducing the antagonistic, but not the agonistic, binding of beta-amino acids. Our data support a model in which the partial agonism of beta-amino acids results from their self-inhibitory activity.