title: Nanomolar allopregnanolone potentiates rat cerebellar GABAA receptors.
abstract: The ionophore function of gamma-aminobutyric acid A (GABA(A)) receptors was studied by whole-cell patch clamp electrophysiology in primary cultures of rat cerebellar cortex. Chloride currents elicited by 1 microM GABA were potentiated by allopregnanolone with a plateau of high affinity (EC(50) = 14 nM) and a peak of potentiation around 1 microM allopregnanolone. Furosemide (0.1 mM) eliminated the high affinity phase and increased the EC(50) to 685 nM. GABA(A) receptors of rat cerebellar synaptosomal membranes were labelled with [(3)H]ethynylbicycloorthobenzoate (EBOB). Allopregnanolone displaced [(3)H]EBOB binding with IC(50) = 320 nM. The displacing potency of allopregnanolone was strongly enhanced (IC(50) = 39 nM) in the presence of 400 nM GABA and 60 nM SR 95531. Nanomolar potentiation by allopregnanolone can be associated with cerebellar GABA(A) receptors containing alpha(6), beta(2-3) and delta subunits. This might be suitable for physiological modulation of tonic inhibitory neurotransmission via extrasynaptic GABA(A) receptors in cerebellar granule cells by neurosteroids.
authors.affiliation: Pharmacological Research, Gedeon Richter Ltd., Budapest, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Fodor
authors.forename: Tímea
authors.initials: T
authors.lastname: Bíró
authors.forename: Gábor
authors.initials: G
authors.lastname: Maksay
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001667:Binding, Competitive / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics; D002478:Cells, Cultured; D002525:Cerebellar Cortex / Q000166:cytology* / Q000187:drug effects; D002712:Chlorides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005665:Furosemide / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques / Q000379:methods; D011280:Pregnanolone / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D002712:Chlorides; D018756:GABA Antagonists; D011724:Pyridazines; D011963:Receptors, GABA-A; C091518:1-(4-ethynylphenyl)-4-propyl-2,6,7-trioxabicyclo(2.2.2)octane; D005680:gamma-Aminobutyric Acid; D005665:Furosemide; C049853:gabazine; D011280:Pregnanolone