Functional pharmacology of GABAA receptors containing the chicken brain ?4 subunit

Abstract

The functional pharmacology of receptors composed of the chicken brain {GABAA} receptor γ4 subunit and the mammalian {GABAA} receptor α3 and β2 subunits was studied by heterologous expression in Xenopus laevis oocytes using the two electrode voltage-clamp technique. GABA-evoked currents had an {EC50} of 180±30 μM. Responses were blocked by the competitive and non-competitive {GABAA} receptor antagonists, bicuculline methochloride and picrotoxin. Sodium pentobarbital reversibly potentiated the current several-fold, and Zn2+ ions blocked the current with high potency (IC50=20 μM). 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-β-carboline-3-carboxylate (β-CCM) and methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM) reduced the current. However, the imidazobenzodiazepine Ro 15-4513, which acts as an inverse agonist at mammalian αxβyγ2 {GABAA} receptors (where x=1, 2, 3 or 5, and y=1, 2 or 3), acted as a positive agonist at the γ4 subunit-containing receptors