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1 Subunit of
-Aminobutyric AcidA Receptors Influence Affinities for
Benzodiazepine Binding Site Ligands
Department of Pharmacology, University of Bern, CH-3010 Bern,
Switzerland
Ligands of the benzodiazepine binding site allosterically modulate
-aminobutyric acidA receptors. Their binding pocket is made up of amino acid residues located on both 
and subunits. We
transiently expressed wild-type 1
22 and mutant
GABAA receptors in human embryonic kidney 293 cells and
determined their binding properties. Receptors containing the mutant
Y209A showed ~40-fold decrease in affinity for
[3H]Ro 15-1788 and diazepam, whereas zolpidem displayed
no measurable affinity. Receptors containing the mutant Y209F showed
a small-to-moderate decrease in affinity for [3H]Ro
15-1788, diazepam, zolpidem,
methyl-6,7-dimethoxy-4-ethyl--carboline-3-carboxylate, and Cl
218872, amounting to 2-8-fold. Receptors containing the mutant
Y209Q appeared in the surface membrane of transfected cells, bound
[3H]muscimol with wild-type affinity, but failed to bind
[3H]Ro 15-1788 or [3H]flunitrazepam with
detectable affinity. If these mutant receptors were expressed in
Xenopus laevis oocytes, the apparent affinity for GABA
was only slightly decreased, whereas the ability of the currents to be
stimulated by low concentrations of flunitrazepam was abolished.
Receptors containing a point mutant of another amino acid residue,
T206A, surprisingly showed an increase in affinity of 5- and
16-fold, for the negative allosteric modulator methyl-6,7-dimethoxy-4-ethyl--carboline-3-carboxylate and the partial positive allosteric modulator Cl 218872, respectively, whereas
there was only a small decrease in affinity for Ro 15-1788, diazepam,
and zolpidem, amounting to 2-, 4-, and 5-fold. Both 206 and 209
are thus both important in determining the binding affinities for
ligands of the benzodiazepine binding site. The residues are spaced at
an interval of three amino acids and may be part of an helix.
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