ABSTRACT

Exploitation of γ-aminobutyric acid (GABAA) receptor structural heterogeneity has proved a challenging problem. The observation that internalised GABAA receptors, which are associated with clathrin, appear to be uncoupled from the benzodiazepine sites, brings the story temptingly back to the beginning of this discussion. The use of both ‘knock-out’ and ‘knock-in’ techniques will be discussed as will the studies that have shed light on the problems of tolerance associated with agents that produce their overt effects through interaction with the GABAA receptors. Early radioligand binding studies characterised the GABAA receptors in mammalian brain membranes using either [H]-GABA or its conformationally restricted analogue [H]-muscimol. The only receptor homo-oligomer that responds robustly to GABA is that comprising the ? subunit, which although it is blocked by picrotoxin, is insensitive to the antagonist bicuculline, the barbiturates and the benzodiazepines.