The gamma 3-subunit of the GABAA-receptor confers sensitivity to benzodiazepine receptor ligands.
The gamma 3-subunit of the GABAA-receptor in rat brain has been identified by molecular cloning. When co-expressed with the alpha 5- and beta 2-subunits in transfected cells a high potency for GABA (Ka = 4.9 +/- 1.2 microM) and a strong cooperativity in gating the channel (H = 1.9 +/- 0.2) was observed. The GABA response was potentiated in the presence of flunitrazepam and reduced by beta CCM. An analogous bi-directional modulation of the GABA response was observed with diazepam and DMCM as tested with the subunit combinations alpha 1 beta 2 gamma 3 and alpha 3 beta 2 gamma 3 expressed in Xenopus oocytes. Since the benzodiazepine receptor ligands were virtually inactive in the absence of the gamma 3-subunit, as tested with the alpha 3 beta 2- and alpha 5 beta 2-subunit combinations, the gamma 3-subunit is a prerequisite for the benzodiazepine receptor sensitivity of the expressed GABAA-receptors. The gamma 3-subunit could functionally replace the gamma 2-subunit with regard to the bi-directional allosteric drug modulation.
Knoflach
F
F
Institute of Pharmacology, University of Zürich, Switzerland.
Rhyner
T
T
Villa
M
M
Kellenberger
S
S
Drescher
U
U
Malherbe
P
P
Sigel
E
E
Möhler
H
H
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001569:Benzodiazepines / Q000378:metabolism* / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D003001:Cloning, Molecular; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005445:Flunitrazepam / Q000494:pharmacology; D008969:Molecular Sequence Data; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects / Q000235:genetics*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid; D005445:Flunitrazepam; D003975:Diazepam