GABAA-receptor expressed from rat brain alpha- and beta-subunit cDNAs displays potentiation by benzodiazepine receptor ligands.
In mammalian brain, the activation of GABAA-receptors is associated with the opening of chloride channels, whose function can be allosterically modulated by drugs, in particular by ligands of the benzodiazepine receptor. Agonistic ligands potentiate while inverse agonists reduce the efficiency of GABA. We have cloned cDNAs encoding alpha 1- and beta 1-subunits of the GABAA-receptor from rat brain. When the corresponding RNAs were co-expressed in Xenopus oocytes. GABA-induced currents were recorded which were inhibited by bicuculline and potentiated by pentobarbital. GABA activated the channel in a weakly cooperative manner. Furthermore, the GABA-response was modulated by benzodiazepine receptor ligands. However, not only various agonists but also the antagonist flumazenil and the inverse agonist DMCM potentiated the GABA-response. Thus, alpha 1- and beta 1-subunits are sufficient to form GABAA-receptors which contain benzodiazepine binding sites, although in a functionally restricted form.
Malherbe
P
P
Research Department, F. Hoffmann-La Roche, Basel, Switzerland.
Draguhn
A
A
Multhaup
G
G
Beyreuther
K
K
Möhler
H
H
D000595:Amino Acid Sequence; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001483:Base Sequence; D001569:Benzodiazepines; D001921:Brain / Q000378:metabolism*; D002417:Cattle; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D003001:Cloning, Molecular; D005333:Fetus; D015723:Gene Library; D006801:Humans; D008024:Ligands; D046911:Macromolecular Substances; D008564:Membrane Potentials / Q000187:drug effects; D008969:Molecular Sequence Data; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D011487:Protein Conformation; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D014151:Anti-Anxiety Agents; D008024:Ligands; D046911:Macromolecular Substances; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid