Modulation of GABAA Receptor tert-[35S]Butylbicyclophosphorothionate Binding by Antagonists: Relationship to Patterns of Subunit Expression

Authors

  • E. R. Korpi,

    Corresponding author
    1. Biomedical Research Center, Alko Group Ltd., Helsinki, Finland; and
    Search for more papers by this author
  • P. H. Seeburg,

    1. Center for Molecular Biology, University of Heidelberg, Heidelberg, Germany
    Search for more papers by this author
  • H. Lüddens

    1. Center for Molecular Biology, University of Heidelberg, Heidelberg, Germany
    Search for more papers by this author
    • The present address of Dr. H. Lüddens is Clinical Research Group, Department of Psychiatry, University of Mainz, Verfügungsgebäude, Obere Zahlbacher Strasse 63, D-55101 Mainz, Germany.


Address correspondence and reprint requests to Dr. E. R. Korpi at Biomedical Research Center, Alko Group Ltd., P.O. Box 350, FIN-00101 Helsinki, Finland.

Abstract

Abstract: The multisubunit γ-aminobutyric acid type A (GABAA) receptor is heterogeneous in molecular and pharmacological aspects. We used quantitative autoradiographic techniques to generate detailed pharmacological profiles for the binding of the GABAA-receptor ionophore ligand tert-[35S]butylbicyclophosphorothionate ([35S]TBPS) and its modulation by GABA and the GABAA antagonists bicuculline and 2′-(3′-carboxy-2′,3′-propyl)-3-amino-6-p-methoxyphenylpyrazinium bromide (SR 95531). Regional differences in the actions of bicuculline and SR 95531 were correlated with the expression of 13 GABAA subunits in brain as reported previously. In some brain regions SR 95531 reduced [35S]TBPS binding much more than bicuculline, as illustrated by high ratios of bicuculline- to SR 95531-modulated [35S]TBPS binding. This ratio correlated positively with α2-subunit mRNA levels. Binding that was equally affected by SR 95531 and bicuculline occurred prominently in regions with abundant α1 mRNA expression. The present findings thus reveal a novel pharmacological heterogeneity based on differences between α1 and α2 subunit-containing GABAA receptors. The data aid in developing GABAA-receptor subtype-specific antagonists and in establishing receptor domains critical for the actions of GABAA antagonists.

Ancillary