GABAA-receptor subtypes differing in alpha-subunit composition display unique pharmacological properties.
GABAA-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 [3H]-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.
Mohler
H
H
Institute of Pharmacology, University of Zurich, Switzerland.
Benke
D
D
Mertens
S
S
Fritschy
J M
JM
D000818:Animals; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D011963:Receptors, GABA-A / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*
D008024:Ligands; D011963:Receptors, GABA-A