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Modulation of GABAA receptor tert-[35S butylbicyclophosphorothionate binding by antagonists: relationship to patterns of subunit expression

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Seeburg,  Peter H.
Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society;

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Citation

Korpi, E. R., Seeburg, P. H., & Lüddens, H. (1996). Modulation of GABAA receptor tert-[35S butylbicyclophosphorothionate binding by antagonists: relationship to patterns of subunit expression. Journal of Neurochemistry: official journal of the International Society for Neurochemistry, 66(5), 2179-2187. Retrieved from http://www.jneurochem.org/cgi/content/abstract/66/5/2179.


Cite as: https://hdl.handle.net/11858/00-001M-0000-0024-223E-B
Abstract
The multisubunit gamma−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 alpha2−subunit mRNA levels. Binding that was equally affected by SR 95531 and bicuculline occurred prominently in regions with abundant alpha1 mRNA expression. The present findings thus reveal a novel pharmacological heterogeneity based on differences between alpha1 and alpha2 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