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Vol. 56, Issue 3, 464-472, September 1999
Department of Neurochemistry, Max-Planck Institute for Brain
Research, Frankfurt/Main, Federal Republic of Germany
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
GlyR
1 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 1 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 
-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 1 subunit reducing
the antagonistic, but not the agonistic, binding of -amino acids.
Our data support a model in which the partial agonism of -amino
acids results from their self-inhibitory activity.
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