Targeted Disruption of the GABAA Receptor δ Subunit Gene Leads to an Up-regulation of γ2 Subunit-containing Receptors in Cerebellar Granule Cells

Verena Tretter, Birgit Hauer, Zoltan Nusser, Robert M. Mihalek, Harald Höger, Gregg E. Homanics, Peter Somogyi, Werner Sieghart

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Abstract

GABAA receptors are chloride channels composed of five subunits. Cerebellar granule cells express abundantly six subunits belonging to four subunit classes. These are assembled into a number of distinct receptors, but the regulation of their relative proportions is yet unknown. Here, we studied the composition of cerebellar GABAA receptors after targeted disruption of the δ subunit gene. In membranes and extracts of δ-/- cerebellum, [3H]muscimol binding was not significantly changed, whereas [3H]Ro15-4513 binding was increased by 52% due to an increase in diazepam-insensitive binding. Immunocytochemical and Western blot analysis revealed no change in α6 subunits but an increased expression of γ2 subunits in δ-/- cerebellum. Immunoaffinity chromatography of cerebellar extracts indicated there was an increased coassembly of α6 and γ2 subunits and that 24% of all receptors in δ-/- cerebellum did not contain a γ subunit. Because 97% of δ subunits are coassembled with α6 subunits in the cerebellum of wild-type mice, these results indicated that, in δ-/- mice, α6β2 and αβ receptors replaced δ subunit-containing receptors. The availability of the δ subunit, thus, influences the level of expression or the extent of assembly of the γ2 subunit, although these two subunits do not occur in the same receptor.

Original languageEnglish
Pages (from-to)10532-10538
Number of pages7
JournalJournal of Biological Chemistry
Volume276
Issue number13
DOIs
Publication statusPublished - Mar 30 2001

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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