GABAA-receptor alpha-subunit is an essential prerequisite for receptor formation in vivo.
The mechanisms governing the assembly of alpha-, beta- and gamma-subunits to form GABAA-receptors are poorly understood. Here, we report that the alpha-subunit is essential for receptor assembly. In mice homozygous for a deletion on chromosome 7 spanning the alpha 5- and gamma 3-subunit genes, zolpidem-insensitive benzodiazepine binding sites, corresponding to GABAA-receptors containing the alpha 5-subunit, were absent in the hippocampus. This loss of alpha 5-GABAA-receptor binding was also apparent as a 21% decrease in the total number of benzodiazepine binding sites in the hippocampus. In addition, immunoreactivity for the beta 2,3- and gamma 2-subunit was decreased exclusively in neurons which normally express the alpha 5-subunit, such as olfactory bulb granule cells and hippocampal pyramidal cells. In other brain regions of the mutants, the beta 2,3- and gamma 2-subunit staining was unaffected. Controls included two lines of mice homozygous for a shorter chromosomal deletion, that either included or excluded the gamma 3-subunit gene. These two lines were indistinguishable with regard to numbers of benzodiazepine binding sites and levels alpha 5-, beta 2,3- and gamma 2-subunit immunoreactivity, indicating that the lack of gamma 3-subunit gene did not contribute to the observed deficit in receptor formation. These results demonstrate that the absence of the alpha 5-subunit gene prevents the formation of the entire respective receptor complex in adult mouse brain. Thus, the alpha-subunit, unlike the gamma 2-subunit, might play a major role in the assembly or targeting of GABAA-receptor complexes.
Fritschy
J M
JM
Institute of Pharmacology, University of Zürich, Switzerland.
Benke
D
D
Johnson
D K
DK
Mohler
H
H
Rudolph
U
U
D000818:Animals; D001345:Autoradiography; D001923:Brain Chemistry / Q000187:drug effects / Q000235:genetics*; D002872:Chromosome Deletion; D005442:Flumazenil / Q000378:metabolism; D018757:GABA Modulators / Q000378:metabolism; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007150:Immunohistochemistry; D007700:Kinetics; D008566:Membranes / Q000378:metabolism; D051379:Mice; D009154:Mutation; D011725:Pyridines / Q000494:pharmacology; D011869:Radioligand Assay; D011963:Receptors, GABA-A / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D000077334:Zolpidem
D018757:GABA Modulators; D006993:Hypnotics and Sedatives; D011725:Pyridines; D011963:Receptors, GABA-A; D005442:Flumazenil; D000077334:Zolpidem