High affinity, heterogeneous displacement of [3H]EBOB binding to cerebellar GABAA receptors by neurosteroids and GABA agonists

G. Maksay, Tímea Bíró

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Heterogeneous binding interactions of cerebellar GABAA receptors were investigated with GABA agonists and neurosteroids. GABAA receptors of rat cerebellum were labelled with [3H] ethynylbicycloorthobenzoate (EBOB), a convulsant radioligand. Saturation analysis revealed a homogenous, nanomolar population of [3H]EBOB binding. Both GABA and 5α-tetrahydrodeoxycorticosterone (5α-THDOC) displaced [3H]EBOB binding heterogeneously, with nanomolar and micromolar potencies. The nanomolar phase of displacement by GABA was selectively abolished by 100 μM furosemide. Physiological concentrations of allopregnanolone (8 nM) and 5α-THDOC (20 nM) increased the displacing effects of nanomolar GABA. GABA (0.3 μM) and 5α-THDOC (0.3 μM) potentiated the micromolar population of displacement by the other. Taurine inhibited [3H]EBOB binding also heterogeneously, with micromolar and millimolar potencies, and 0.3 μM 5α-THDOC potentiated this inhibition. 5β-THDOC did not affect [3H]EBOB binding significantly but in 1 μM it antagonised selectively the nanomolar displacement by 5α-THDOC. [3H]EBOB binding to hippocampal GABAA receptors was inhibited by GABA and allopregnanolone with low (micromolar) potencies and with slope values higher than unity referring to allosteric interaction. High affinity displacement of cerebellar [3H]EBOB binding by GABA agonists and neurosteroids can be associated with constitutively open α6βδ GABAA receptors, tonic GABAergic inhibitory neurotransmission and its modulation by physiological concentrations of neurosteroids.

Original languageEnglish
Pages (from-to)431-438
Number of pages8
JournalNeuropharmacology
Volume49
Issue number4
DOIs
Publication statusPublished - Sep 2005

Fingerprint

GABA-A Receptor Agonists
GABA Agonists
Neurotransmitter Agents
gamma-Aminobutyric Acid
GABA-A Receptors
Pregnanolone
Convulsants
Taurine
Furosemide
Synaptic Transmission
Cerebellum
Population
tetrahydrodeoxycorticosterone

Keywords

  • αβδ GABA receptors
  • [ H]EBOB binding
  • Allopregnanolone
  • Furosemide
  • Taurine
  • THDOC epimers

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Drug Discovery
  • Pharmacology

Cite this

High affinity, heterogeneous displacement of [3H]EBOB binding to cerebellar GABAA receptors by neurosteroids and GABA agonists. / Maksay, G.; Bíró, Tímea.

In: Neuropharmacology, Vol. 49, No. 4, 09.2005, p. 431-438.

Research output: Contribution to journalArticle

@article{3bc767b07d0f4179a1de104004131fdc,
title = "High affinity, heterogeneous displacement of [3H]EBOB binding to cerebellar GABAA receptors by neurosteroids and GABA agonists",
abstract = "Heterogeneous binding interactions of cerebellar GABAA receptors were investigated with GABA agonists and neurosteroids. GABAA receptors of rat cerebellum were labelled with [3H] ethynylbicycloorthobenzoate (EBOB), a convulsant radioligand. Saturation analysis revealed a homogenous, nanomolar population of [3H]EBOB binding. Both GABA and 5α-tetrahydrodeoxycorticosterone (5α-THDOC) displaced [3H]EBOB binding heterogeneously, with nanomolar and micromolar potencies. The nanomolar phase of displacement by GABA was selectively abolished by 100 μM furosemide. Physiological concentrations of allopregnanolone (8 nM) and 5α-THDOC (20 nM) increased the displacing effects of nanomolar GABA. GABA (0.3 μM) and 5α-THDOC (0.3 μM) potentiated the micromolar population of displacement by the other. Taurine inhibited [3H]EBOB binding also heterogeneously, with micromolar and millimolar potencies, and 0.3 μM 5α-THDOC potentiated this inhibition. 5β-THDOC did not affect [3H]EBOB binding significantly but in 1 μM it antagonised selectively the nanomolar displacement by 5α-THDOC. [3H]EBOB binding to hippocampal GABAA receptors was inhibited by GABA and allopregnanolone with low (micromolar) potencies and with slope values higher than unity referring to allosteric interaction. High affinity displacement of cerebellar [3H]EBOB binding by GABA agonists and neurosteroids can be associated with constitutively open α6βδ GABAA receptors, tonic GABAergic inhibitory neurotransmission and its modulation by physiological concentrations of neurosteroids.",
keywords = "αβδ GABA receptors, [ H]EBOB binding, Allopregnanolone, Furosemide, Taurine, THDOC epimers",
author = "G. Maksay and T{\'i}mea B{\'i}r{\'o}",
year = "2005",
month = "9",
doi = "10.1016/j.neuropharm.2005.04.003",
language = "English",
volume = "49",
pages = "431--438",
journal = "Neuropharmacology",
issn = "0028-3908",
publisher = "Elsevier Limited",
number = "4",

}

TY - JOUR

T1 - High affinity, heterogeneous displacement of [3H]EBOB binding to cerebellar GABAA receptors by neurosteroids and GABA agonists

AU - Maksay, G.

AU - Bíró, Tímea

PY - 2005/9

Y1 - 2005/9

N2 - Heterogeneous binding interactions of cerebellar GABAA receptors were investigated with GABA agonists and neurosteroids. GABAA receptors of rat cerebellum were labelled with [3H] ethynylbicycloorthobenzoate (EBOB), a convulsant radioligand. Saturation analysis revealed a homogenous, nanomolar population of [3H]EBOB binding. Both GABA and 5α-tetrahydrodeoxycorticosterone (5α-THDOC) displaced [3H]EBOB binding heterogeneously, with nanomolar and micromolar potencies. The nanomolar phase of displacement by GABA was selectively abolished by 100 μM furosemide. Physiological concentrations of allopregnanolone (8 nM) and 5α-THDOC (20 nM) increased the displacing effects of nanomolar GABA. GABA (0.3 μM) and 5α-THDOC (0.3 μM) potentiated the micromolar population of displacement by the other. Taurine inhibited [3H]EBOB binding also heterogeneously, with micromolar and millimolar potencies, and 0.3 μM 5α-THDOC potentiated this inhibition. 5β-THDOC did not affect [3H]EBOB binding significantly but in 1 μM it antagonised selectively the nanomolar displacement by 5α-THDOC. [3H]EBOB binding to hippocampal GABAA receptors was inhibited by GABA and allopregnanolone with low (micromolar) potencies and with slope values higher than unity referring to allosteric interaction. High affinity displacement of cerebellar [3H]EBOB binding by GABA agonists and neurosteroids can be associated with constitutively open α6βδ GABAA receptors, tonic GABAergic inhibitory neurotransmission and its modulation by physiological concentrations of neurosteroids.

AB - Heterogeneous binding interactions of cerebellar GABAA receptors were investigated with GABA agonists and neurosteroids. GABAA receptors of rat cerebellum were labelled with [3H] ethynylbicycloorthobenzoate (EBOB), a convulsant radioligand. Saturation analysis revealed a homogenous, nanomolar population of [3H]EBOB binding. Both GABA and 5α-tetrahydrodeoxycorticosterone (5α-THDOC) displaced [3H]EBOB binding heterogeneously, with nanomolar and micromolar potencies. The nanomolar phase of displacement by GABA was selectively abolished by 100 μM furosemide. Physiological concentrations of allopregnanolone (8 nM) and 5α-THDOC (20 nM) increased the displacing effects of nanomolar GABA. GABA (0.3 μM) and 5α-THDOC (0.3 μM) potentiated the micromolar population of displacement by the other. Taurine inhibited [3H]EBOB binding also heterogeneously, with micromolar and millimolar potencies, and 0.3 μM 5α-THDOC potentiated this inhibition. 5β-THDOC did not affect [3H]EBOB binding significantly but in 1 μM it antagonised selectively the nanomolar displacement by 5α-THDOC. [3H]EBOB binding to hippocampal GABAA receptors was inhibited by GABA and allopregnanolone with low (micromolar) potencies and with slope values higher than unity referring to allosteric interaction. High affinity displacement of cerebellar [3H]EBOB binding by GABA agonists and neurosteroids can be associated with constitutively open α6βδ GABAA receptors, tonic GABAergic inhibitory neurotransmission and its modulation by physiological concentrations of neurosteroids.

KW - αβδ GABA receptors

KW - [ H]EBOB binding

KW - Allopregnanolone

KW - Furosemide

KW - Taurine

KW - THDOC epimers

UR - http://www.scopus.com/inward/record.url?scp=23844445260&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=23844445260&partnerID=8YFLogxK

U2 - 10.1016/j.neuropharm.2005.04.003

DO - 10.1016/j.neuropharm.2005.04.003

M3 - Article

VL - 49

SP - 431

EP - 438

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

IS - 4

ER -