Functional pharmacology of GABA(A) receptors containing the chicken brain gamma 4 subunit.
The functional pharmacology of receptors composed of the chicken brain GABA(A) receptor gamma 4 subunit and the mammalian GABA(A) receptor alpha 3 and beta2 subunits was studied by heterologous expression in Xenopus laevis oocytes using the two electrode voltage-clamp technique. GABA-evoked currents had an EC(50) of 180+/-30 microM. Responses were blocked by the competitive and non-competitive GABA(A) receptor antagonists, bicuculline methochloride and picrotoxin. Sodium pentobarbital reversibly potentiated the current several-fold, and Zn(2+) ions blocked the current with high potency (IC50=20 microM). GABA-evoked currents were potentiated by the benzodiazepine site full agonists flunitrazepam and triazolam and less by the partial agonists abecarnil and bretazenil. The inverse agonists methyl-beta-carboline-3-carboxylate (beta-CCM) and methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) reduced the current. However, the imidazobenzodiazepine Ro 15-4513, which acts as an inverse agonist at mammalian alphaxbetaygamma2 GABA(A) receptors (where x=1, 2, 3 or 5, and y=1, 2 or 3), acted as a positive agonist at the gamma 4 subunit-containing receptors.
Forster
I C
IC
Physiologisches Institut der Universität Zürich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland. IForster@access.unizh.ch
Harvey
R J
RJ
Darlison
M G
MG
Benson
J A
JA
D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D001923:Brain Chemistry; D002645:Chickens; D004305:Dose-Response Relationship, Drug; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology*; D006801:Humans; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010424:Pentobarbital / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D021122:Protein Subunits; D011963:Receptors, GABA-A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014982:Xenopus laevis; D015032:Zinc / Q000737:chemistry / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D001640:Bicuculline; D018755:GABA Agonists; D018756:GABA Antagonists; D018757:GABA Modulators; D010424:Pentobarbital; D010852:Picrotoxin; D021122:Protein Subunits; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D015032:Zinc; D005680:gamma-Aminobutyric Acid