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The Journal of Neuroscience, February 14, 2007, 27(7):1692-1701; doi:10.1523/JNEUROSCI.3155-06.2007

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Cellular/Molecular
Phosholipase C-Related Inactive Protein Is Involved in Trafficking of 2 Subunit-Containing GABA_A Receptors to the Cell Surface

Akiko Mizokami,¹ Takashi Kanematsu,¹ Hitoshi Ishibashi,² Taku Yamaguchi,⁴ Isei Tanida,⁵ Kei Takenaka,⁶ Keiichi I. Nakayama,³ Kiyoko Fukami,⁷ Tadaomi Takenawa,⁶ Eiki Kominami,⁵ Stephen J. Moss,⁸ Tsuneyuki Yamamoto,⁹ Junichi Nabekura,¹⁰ and Masato Hirata¹

¹Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, and Station for Collaborative Research, ²Department of Cellular and System Physiology, Faculty of Medical Science, and ³Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan, ⁴Department of Neuropharmacology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan, ⁵Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan, ⁶Department of Biochemistry, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan, ⁷Laboratory of Genome and Biosignal, Tokyo University of Pharmacy and Life Science, Tokyo 192-0392, Japan, ⁸Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, ⁹Department of Pharmacology, Faculty of Pharmaceutical Science, Nagasaki International University, Nagasaki 859-3298, Japan, and ¹⁰Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki 444-8585, Japan

Correspondence should be addressed to Dr. Masato Hirata, Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, and Station for Collaborative Research, Kyushu University, Fukuoka 812-8582, Japan. Email: hirata1{at}dent.kyushu-u.ac.jp

The subunit composition of GABA_A receptors is known to be associated with distinct physiological and pharmacological properties. Previous studies that used phospholipase C-related inactive protein type 1 knock-out (PRIP-1 KO) mice revealed that PRIP-1 is involved in the assembly and/or the trafficking of 2 subunit-containing GABA_A receptors. There are two PRIP genes in mammals; thus the roles of PRIP-1 might be compensated partly by those of PRIP-2 in PRIP-1 KO mice. Here we used PRIP-1 and PRIP-2 double knock-out (PRIP-DKO) mice and examined the roles for PRIP in regulating the trafficking of GABA_A receptors. Consistent with previous results, sensitivity to diazepam was reduced in electrophysiological and behavioral analyses of PRIP-DKO mice, suggesting an alteration of 2 subunit-containing GABA_A receptors. The surface numbers of diazepam binding sites (/2 subunits) assessed by [³H]flumazenil binding were reduced in the PRIP-DKO mice as compared with those of wild-type mice, whereas the cell surface GABA binding sites (/ß subunits, assessed by [³H]muscimol binding) were increased in PRIP-DKO mice. The association between GABA_A receptors and GABA_A receptor-associated protein (GABARAP) was reduced significantly in PRIP-DKO neurons. Disruption of the direct interaction between PRIP and GABA_A receptor ß subunits via the use of a peptide corresponding to the PRIP-1 binding site reduced the cell surface expression of 2 subunit-containing GABA_A receptors in cultured cell lines and neurons. These results suggest that PRIP is implicated in the trafficking of 2 subunit-containing GABA_A receptors to the cell surface, probably by acting as a bridging molecule between GABARAP and the receptors.

Key words: benzodiazepine; GABA_A receptor; GABARAP; knock-out mice; PRIP; trafficking

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Received July 24, 2006; revised Dec. 15, 2006; accepted Jan. 8, 2007.

Correspondence should be addressed to Dr. Masato Hirata, Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, and Station for Collaborative Research, Kyushu University, Fukuoka 812-8582, Japan. Email: hirata1{at}dent.kyushu-u.ac.jp

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