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GABA A receptor subunit alteration‐dependent diazepam insensitivity in the cerebellum of phospholipase C‐related inactive protein knockout mice
Author(s) -
Mizokami Akiko,
Tanaka Hiroto,
Ishibashi Hitoshi,
Umebayashi Hisanori,
Fukami Kiyoko,
Takenawa Tadaomi,
Nakayama Keiichi I.,
Yokoyama Takeshi,
Nabekura Junichi,
Kanematsu Takashi,
Hirata Masato
Publication year - 2010
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2010.06754.x
Subject(s) - knockout mouse , cerebellum , protein subunit , chemistry , receptor , phospholipase c , gabaa receptor , neuroscience , microbiology and biotechnology , endocrinology , medicine , biology , biochemistry , gene
J. Neurochem. (2010) 114 , 302–310. Abstract The GABA A 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 GABA A 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) GABA A receptors in the cerebellar granule cells.