title: Ligand-gated ion channel subunit partnerships: GABAA receptor alpha6 subunit gene inactivation inhibits delta subunit expression.
abstract: Cerebellar granule cells express six GABAA receptor subunits abundantly (alpha1, alpha6, beta2, beta3, gamma2, and delta) and assemble various pentameric receptor subtypes with unknown subunit compositions; however, the rules guiding receptor subunit assembly are unclear. Here, removal of intact alpha6 protein from cerebellar granule cells allowed perturbations in other subunit levels to be studied. Exon 8 of the mouse alpha6 subunit gene was disrupted by homologous recombination. In alpha6 -/- granule cells, the delta subunit was selectively degraded as seen by immunoprecipitation, immunocytochemistry, and immunoblot analysis with delta subunit-specific antibodies. The delta subunit mRNA was present at wild-type levels in the mutant granule cells, indicating a post-translational loss of the delta subunit. These results provide genetic evidence for a specific association between the alpha6 and delta subunits. Because in alpha6 -/- neurons the remaining alpha1, beta2/3, and gamma2 subunits cannot rescue the delta subunit, certain potential subunit combinations may not be found in wild-type cells.
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Medical Research Council Centre, Cambridge CB2 2QH, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: Jones
authors.forename: E R
authors.initials: ER
authors.lastname: Korpi
authors.forename: R M
authors.initials: RM
authors.lastname: McKernan
authors.forename: R
authors.initials: R
authors.lastname: Pelz
authors.forename: Z
authors.initials: Z
authors.lastname: Nusser
authors.forename: R
authors.initials: R
authors.lastname: Mäkelä
authors.forename: J R
authors.initials: JR
authors.lastname: Mellor
authors.forename: S
authors.initials: S
authors.lastname: Pollard
authors.forename: S
authors.initials: S
authors.lastname: Bahn
authors.forename: F A
authors.initials: FA
authors.lastname: Stephenson
authors.forename: A D
authors.initials: AD
authors.lastname: Randall
authors.forename: W
authors.initials: W
authors.lastname: Sieghart
authors.forename: P
authors.initials: P
authors.lastname: Somogyi
authors.forename: A J
authors.initials: AJ
authors.lastname: Smith
authors.forename: W
authors.initials: W
authors.lastname: Wisden
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001569:Benzodiazepines / Q000494:pharmacology; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018755:GABA Agonists / Q000378:metabolism; D018756:GABA Antagonists / Q000378:metabolism; D058787:GABA-A Receptor Antagonists; D005786:Gene Expression Regulation; D015640:Ion Channel Gating; D007473:Ion Channels / Q000378:metabolism*; D007763:Lac Operon; D008024:Ligands; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D009118:Muscimol / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011724:Pyridazines / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics* / Q000378:metabolism
chemical_list: D018755:GABA Agonists; D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D007473:Ion Channels; D008024:Ligands; D011724:Pyridazines; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D009118:Muscimol; C049853:gabazine