GABAA Receptor Populations Bind Agonists and Antagonists Differentially and with Opposite Affinities

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Abstract

Abstract: Pretreatment of synaptosomal membranes with a diazo‐coupling reagent and the presence of CI ions were used to differentiate high‐ and low‐affinity populations of postsynaptic γ‐aminobutyric acid (GABAA) receptors. The super‐low‐affinity GABAA receptors were characterized by the enhancing effect of GABA on [3H]diazepam binding. The GABA antagonists 2–(3‐carboxypropyl)‐3‐amino‐4‐methyl‐6‐phenylpyridazinium chloride (SR 95103) and 3‐α‐hydroxy‐16‐imino‐5β‐17‐aza‐androstan‐11‐one (R 5135) shifted and suppressed the dose‐response curve of GABA on diazepam binding. SR 95103 displaced the lower affinity [3H]GABA binding with higher potency. Dissociation of the binding of the antagonist 2–(3‐carboxypropyl)‐3‐amino‐6‐p‐methoxyphenylpyridazinium bromide ([3H]SR 95531) was polyphasic. Displacing potencies of SR 95531 and GABA were examined on the major (85%) rapid and minor slower phases of dissociation separated kinetically. The slower phase corresponded to higher affinity binding of SR 95531 which was displaced by GABA with about 10 times less potency. Photoaffinity labeling with muscimol decreased the number of [3H]muscimol binding sites by 27%. It decreased the displacing potency of GABA by 72%, but not that of bicuculline methiodide. These findings can be explained by a preferential binding of antagonists to hydrophobic accessory sites around low‐affinity GABAA receptors.

Original languageEnglish
Pages (from-to)1865-1871
Number of pages7
JournalJournal of neurochemistry
Volume50
Issue number6
DOIs
Publication statusPublished - Jun 1988

Keywords

  • Dissociation of SR 95531 binding
  • GABA receptor populations
  • GABA‐enhanced diazepam binding
  • Muscimol photoaffinity labeling
  • Pyridazinyl‐GABA antagonists

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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