GABAA receptor subunit alteration-dependent diazepam insensitivity in the cerebellum of phospholipase C-related inactive protein knockout mice

Akiko Mizokami, Hiroto Tanaka, Hitoshi Ishibashi, Hisanori Umebayashi, Kiyoko Fukami, Tadaomi Takenawa, Keiichi I. Nakayama, Takeshi Yokoyama, Junichi Nabekura, Takashi Kanematsu, Masato Hirata

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

The GABAA receptor, a pentamer composed predominantly of α, β, and γ subunits, mediates fast inhibitory synaptic transmission. We have previously reported that phospholipase C-related inactive protein (PRIP) is a modulator of GABAA receptor trafficking and that knockout (KO) mice exhibit a diazepam-insensitive phenotype in the hippocampus. The α subunit affects diazepam sensitivity; α1, 2, 3, and 5 subunits assemble with any form of β and the γ2 subunits to produce diazepam-sensitive receptors, whereas α4 or α6/β/γ2 receptors are diazepam-insensitive. Here, we investigated how PRIP is implicated in the diazepam-insensitive phenotype using cerebellar granule cells in animals expressing predominantly the α6 subunit. The expression of α1/β/γ2 diazepam-sensitive receptors was decreased in the PRIP-1 and 2 double KO cerebellum without any change in the total number of benzodiazepine-binding sites as assessed by radioligand-binding assay. Since levels of the α6 subunit were increased, the α1/β/γ2 receptors might be replaced with α6 subunit-containing receptors. Then, we further performed autoradiographic and electrophysiologic analyses. These results suggest that the expression of α6/δ receptors was decreased in cerebellar granule neurons, while that of α6/γ2 receptors was increased. PRIP-1 and 2 double KO mice exhibit a diazepam-insensitive phenotype because of a decrease in diazepam-sensitive (α1/γ2) and increase in diazepam-insensitive (α6/γ2) GABAA receptors in the cerebellar granule cells.

Original languageEnglish
Pages (from-to)302-310
Number of pages9
JournalJournal of Neurochemistry
Volume114
Issue number1
DOIs
Publication statusPublished - Jul 2010

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cellular and Molecular Neuroscience

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