title: Characterization of gamma-aminobutyrate type A receptors with atypical coupling between agonist and convulsant binding sites in discrete brain regions.
abstract: Gamma-ainobutyric acid type A (GABA(A)) receptor ionophore ligand t-[35S]butylbicyclophosphorothionate ([35S]TBPS) was used in an autoradiographic assay on brain cryostat sections to visualize and characterize atypical GABA-insensitive [35S]TBPS binding previously described in certain recombinant GABA(A) receptors and the cerebellar granule cell layer. Picrotoxinin-sensitive but 1-mM GABA-insensitive [35S]TBPS binding was present in the rat cerebellar granule cell layer, many thalamic nuclei, subiculum and the internal rim of the cerebral cortex, amounting in these regions up to 6% of the basal binding determined in the absence of exogenous GABA. Similar binding properties were detected also in human and chicken brain sections. Like the GABA-sensitive [35S]TBPS binding, GABA-insensitive binding was profoundly decreased by pentobarbital, pregnanolone, loreclezole and Mg2+. The binding was reversible and apparently dependent on Cl- ions. Localization of the GABA-insensitive [35S]TBPS binding was not identical to that of high-affinity [3H]muscimol binding and diazepam-insensitive [3H]Ro 15-4513 binding, two previously established receptor subtype-dependent binding heterogeneities in the rat brain. The present study reveals a component of the GABA-ionophore enriched in the thalamus and cerebellar granule cells, possibly representing poorly desensitized or desensitizing receptors.
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland.
authors.forename: S T
authors.initials: ST
authors.lastname: Sinkkonen
authors.forename: M
authors.initials: M
authors.lastname: Uusi-Oukari
authors.forename: E
authors.initials: E
authors.lastname: Tupala
authors.forename: T
authors.initials: T
authors.lastname: Särkioja
authors.forename: J
authors.initials: J
authors.lastname: Tiihonen
authors.forename: P
authors.initials: P
authors.lastname: Panula
authors.forename: H
authors.initials: H
authors.lastname: Lüddens
authors.forename: E R
authors.initials: ER
authors.lastname: Korpi
mesh_terms: D000345:Affinity Labels / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001386:Azides / Q000378:metabolism / Q000494:pharmacology; D001569:Benzodiazepines / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism / Q000494:pharmacology*; D002531:Cerebellum / Q000378:metabolism*; D002645:Chickens; D003292:Convulsants / Q000378:metabolism / Q000494:pharmacology*; D018755:GABA Agonists / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009118:Muscimol / Q000378:metabolism / Q000494:pharmacology*; D010852:Picrotoxin / Q000031:analogs & derivatives / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*; D054830:Sesterterpenes; D013462:Sulfur Radioisotopes; D013788:Thalamus / Q000378:metabolism*; D014316:Tritium; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D000345:Affinity Labels; D001386:Azides; D001569:Benzodiazepines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003292:Convulsants; D018755:GABA Agonists; D009118:Muscimol; D010852:Picrotoxin; D011963:Receptors, GABA-A; D054830:Sesterterpenes; D013462:Sulfur Radioisotopes; D014316:Tritium; D005680:gamma-Aminobutyric Acid; C037476:tert-butylbicyclophosphorothionate; C042957:Ro 15-4513; C022961:picrotoxinin