The α5(H105R) mutation impairs α5 selective binding properties by altered positioning of the α5 subunit in GABAA receptors containing two distinct types of α subunits

Ela Balic, Uwe Rudolph, Jean Marc Fritschy, Hanns Mohler, Dietmar Benke

Research output: Contribution to journalArticlepeer-review

Abstract

GABAA receptors are pentameric ligand-gated ion channels that are major mediators of fast inhibitory neurotransmission. Clinically relevant GABAA receptor subtypes are assembled from α5(1-3, 5), β1-3 and the γ2 subunit. They exhibit a stoichiometry of two α, two β and one γ subunit, with two GABA binding sites located at the α/β and one benzodiazepine binding site located at the α/γ subunit interface. Introduction of the H105R point mutation into the α5 subunit, to render α5 subunit-containing receptors insensitive to the clinically important benzodiazepine site agonist diazepam, unexpectedly resulted in a reduced level of α5 subunit protein in α5(H105R) mice. In this study, we show that the α5(H105R) mutation did not affect cell surface expression and targeting of the receptors or their assembly into macromolecular receptor complexes but resulted in a severe reduction of α5-selective ligand binding. Immunoprecipitation studies suggest that the diminished α5-selective binding is presumably due to a repositioning of the α5(H105R) subunit in GABAA receptor complexes containing two different α subunits. These findings imply an important role of histidine 105 in determining the position of the α5 subunit within the receptor complex by determining the affinity for assembly with the γ2 subunit.

Original languageEnglish (US)
Pages (from-to)244-254
Number of pages11
JournalJournal of Neurochemistry
Volume110
Issue number1
DOIs
StatePublished - Jul 2009
Externally publishedYes

Keywords

  • Assembly
  • GABA receptor
  • Knock-in mice
  • Mutation
  • Targeting
  • α5 subunit

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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