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Regional distribution and subunit composition of GABAA receptors exhibiting atypical GABA partial agonism

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Title: Regional distribution and subunit composition of GABAA receptors exhibiting atypical GABA partial agonism
Author(s): Halonen, Lauri
Contributor: University of Helsinki, Faculty of Medicine, Institute of Biomedicine
Discipline: Pharmacology
Language: English
Acceptance year: 2011
Abstract:
γ-Aminobutyric acid type A (GABAA) receptors are ligand gated ion channels mediating most inhibitory signals in the brain. GABAA receptor consists of five subunits, and there are 16 different subunits known. This forms base to pharmacological diversity of GABAA receptors. In this study autoradiography on subunit gene knock out mouse models was used to visualize the meaning of different subunits in forming GABAA receptors exhibiting special kinds of pharmacology, ie. GABA-insensitive [35S]TBPS-binding and high-affinity [3H]muscimol binding. In receptors exhibiting GABA-insensitive TBPS-binding GABA fails to cause full dissociation of TBPS from the ionophore, which means that the receptors are not fully activated by GABA. This study revealed, that contrary to what was previously believed, the forebrain GABA-insensitive [35S]TBPS binding is most likely caused by GABAA receptors consisting of α1 and β subunits or α1, β and δ subunits. High-affinity muscimol binding in the α1 KO mice was found to be unaltered, whereas α4 KO, δ KO and α4 + δ KO mice exhibited diminished high-affinity [3H]muscimol binding. Contrary to what was previously considered, this study points out that α1β GABAA receptors are mediating GIS-binding in the forebrain. Changes in high-affinity [3H]muscimol binding has also been found to correlate with changes of muscimols effects in vivo in knock out mouse models.


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