Electrophysiological characterization of diazepam binding inhibitor (DBI) on GABAA receptors

Abstract

The gamma-aminobutyric acid (GABAA) receptor complex is a hetero-oligomeric protein which contains an integral chloride channel and several modulatory domains. The ligands of benzodiazepine recognition sites can up- or down-regulate the activity of the GABAA receptor. The effects of DBI (diazepam binding inhibitor) on GABAA receptors have been studied in cultured mammalian central neurons. Experiments performed with patch-clamp techniques, as well as with conventional intracellular microelectrodes, have revealed a reversible reduction of GABA-induced responses by micromolar concentrations of DBI. This effect was prevented by Ro 15-1788 (flumazenil), a selective benzodiazepine receptor antagonist. From these data, DBI is capable of reducing the activity of the GABAA receptor complex by specifically interacting with the benzodiazepine recognition site. The idea of DBI being a negative allosteric modulator of GABAA receptor channels is in agreement with biochemical, as well as behavioral, pharmacology data.