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GABA A Receptors Containing the α4‐Subunit: Prevalence, Distribution, Pharmacology, and Subunit Architecture In Situ
Author(s) -
Benke Dietmar,
Michel Claudia,
Mohler Hanns
Publication year - 1997
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1997.69020806.x
Subject(s) - receptor , protein subunit , forebrain , gabaa receptor , cys loop receptors , interleukin 10 receptor, alpha subunit , gamma aminobutyric acid receptor subunit alpha 1 , diazepam , biology , interleukin 5 receptor alpha subunit , chemistry , biochemistry , pharmacology , g alpha subunit , endocrinology , acetylcholine receptor , central nervous system , nicotinic acetylcholine receptor , gene
Recombinant GABA A receptors, expressed from α‐, β‐, and γ2‐subunits, are diazepam‐insensitive when the α‐subunit is either α4 or α6. In situ, diazepam‐insensitive receptors containing the α6‐subunit are almost exclusively expressed in the granule cell layer of the cerebellum. However, diazepam‐insensitive receptors are also expressed in forebrain areas. Here, we report on the presence of diazepam‐insensitive GABA A receptors in various brain areas containing the α4‐subunit. GABA A receptors immunoprecipitated with a newly developed α4‐subunit‐specific antiserum displayed a drug binding profile that was indistinguishable from those of α4β2γ2‐recombinant receptors and diazepam‐insensitive [ 3 H]Ro 15‐4513 binding sites in rat brain membranes. In addition, α4‐subunit containing receptors and forebrain diazepam‐insensitive receptors are present at comparably low abundance in rat brain and exhibit virtually identical patterns of distribution. Analysis of the subunit architecture of α4‐subunit containing receptors revealed that the α4‐subunit contributes to several receptor subtypes. Depending on the brain region, the α4‐subunit can be coassembled with a second type of α4‐subunit variant being α1, α2, or α3. The data demonstrate that native receptors containing the α4‐subunit are structurally heterogeneous, expressed at very low abundance in the brain, and display the drug binding profile of diazepam‐insensitive [ 3 H]Ro 15‐4513 binding sites. Pharmacologically, these receptors may contribute to the actions of nonclassical ligands such as Ro 15‐4513 and bretazenil.