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Vol. 56, Issue 3, 464-472, September 1999

A Novel Domain of the Inhibitory Glycine Receptor Determining Antagonist Efficacies: Further Evidence for Partial Agonism Resulting from Self-Inhibition

Volker Schmieden,1 Jochen Kuhse,2 and Heinrich Betz

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 GlyRalpha 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 alpha 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 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 alpha 1 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.

Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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