GABA(A)-RECEPTOR SUBTYPES DIFFERING IN ALPHA-SUBUNIT COMPOSITION DISPLAY UNIQUE PHARMACOLOGICAL PROPERTIES

GABA(A)-receptor subtypes in rat brain were characterized using anti-peptide antisera specific for the alpha-1-, alpha-3- and alpha-5-subunits. While a high abundance of alpha-1-containing receptors was demonstrated by immunoprecipitation (80-90% of receptors), the receptors precipitated with the alpha-3- and the alpha-5-antiserum were less frequent (18-25% and 10-23%, respectively). The three receptor populations displayed unique pharmacological properties as shown by radioligand binding. Diazepam, flumazenil and flunitrazepam displayed similar displacing potencies in [H-3]-flumazenil binding. However, the affinities of CL 218872, beta-CCM and zolpidem were up to 10-fold lower in the alpha-3- than the alpha-1-receptor population while intermediate values were found for the alpha-5-receptor population. In many brain areas, a neuron-specific expression of receptors containing either alpha-1- or alpha-3-subunits could be visualized immunohistochemically. It will be of major interest to determine, whether ligands with differential affinities for receptor subtypes in situ will provide novel therapeutic profiles.