RT Journal Article
SR Electronic
T1 Cerebellar γ-Aminobutyric Acid Type A Receptors: Pharmacological Subtypes Revealed by Mutant Mouse Lines
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 380
OP 388
DO 10.1124/mol.52.3.380
VO 52
IS 3
A1 Riikka Mäkelä
A1 Mikko Uusi-Oukari
A1 Gregg E. Homanics
A1 Joseph J. Quinlan
A1 Leonard L. Firestone
A1 William Wisden
A1 Esa R. Korpi
YR 1997
UL http://molpharm.aspetjournals.org/content/52/3/380.abstract
AB The vast molecular heterogeneity of brain γ-aminobutyric acid type A (GABAA) receptors forms the basis for receptor subtyping. Using autoradiographic techniques, we established the characteristics of cerebellar granule cell GABAA receptors by comparing wild-type mice with those with a targeted disruption of the α6 subunit gene. Cerebellar granule cells of α6−/− animals have severe deficits in high affinity [3H]muscimol and [3H]SR 95531 binding to GABA sites, in agonist-insensitive [3H]Ro 15–4513 binding to benzodiazepine sites, and in furosemide-induced increases intert-[35S]butylbicyclophosphorothionate binding to picrotoxin-sensitive convulsant sites. These observations agree with the known specific properties of these sites on recombinant α6β2/3γ2 receptors. In the presence of GABA concentrations that fail to activate α1 subunit-containing receptors, methyl-6,7-dimethoxy-4-ethyl-β-carboline (30 μm), allopregnanolone (100 nm), and Zn2+ (10 μm) are less efficacious in alteringtert-[35S]butylbicyclophosphorothionate binding in the granule cell layer of the α6−/− than α6+/+ animals. These data concur with the deficiency of the cerebellar α6 and δ subunit-containing receptors in the α6−/− animals and could also account for the decreased affinity of [3H]muscimol binding to α6−/−cerebellar membranes. Predicted additional alterations in the cerebellar receptors of the mutant mice may explain a surplus of methyl-6,7-dimethoxy-4-ethyl-β-carboline-insensitive receptors in the α6−/− granule cell layer and an increased diazepam-sensitivity in the molecular layer. These changes may be adaptive consequences of altered GABAA receptor subunit expression patterns in response to the loss of two subunits (α and δ) from granule cells.