GABAA-receptor α-subunit is an essential prerequisite for receptor formation in vivo
Section snippets
Mice
The generation and analysis of mutations at the p locus of chromosome 7, obtained by feeding mice with tritiated water, have been described previously.6, 7, 23The deletions p4THO-II (includes the γ3-, α5-, and β3-subunit genes), p83FBFo (includes the γ3- and α5-subunit genes) and p46DFiOD (includes the γ3-subunit gene) are lethal in the homozygous state. However, p4THO-II/p83FBFo and p4THO-II/p46DFiOD compound heterozygotes are viable. The compound heterozygotes p4THO-II/p 83FBFo are thus
Number and affinity of benzodiazepine binding sites in mutant mice
To assess potential differences in the number of benzodiazepine binding sites in brains of α5−γ3− mutant, γ3− mutant and control mice, radioligand binding assays were performed with crude homogenates from the hippocampus with [3H]flumazenil (Table 1). This region was selected because it contains the highest density of α5-GABAA-receptors in the brain.15, 18Scatchard analysis of the binding data revealed a 21% reduction in the number of binding sites (Bmax) for [3H]flumazenil, with no change in
Discussion
Studies on the contributions of individual GABAA-receptor subunit variants for receptor assembly, cell-surface expression and subcellular targeting have so far been conducted in non-neuronal cell lines and have yielded conflicting results. Perez-Velasquez and Angelides[25]first showed that both the α1- and the β1-subunit are able to form homomeric receptors in epithelial cells (MDCK cells), and that upon co-transfection of the α1β1-subunit cDNAs receptor complexes are targeted towards the
Acknowledgements
The submitted manuscript has been authorized by a contractor of the U.S. Government under contract No. DE-AC05-96OR22464. Accordingly, the U.S. Government retains a non-exclusive, royalty-free license to publish or reproduce the published form of this contribution, or allow others to do so, for U.S. Government purposes. We are grateful to O. Weinmann and C. Michel for their expert technical assistance and to Dr T. Bächi for support with confocal scanning laser microscopy. This research was
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