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J. Biol. Chem., Vol. 281, Issue 31, 22180-22189, August 4, 2006

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Modulation of GABA_A Receptor Phosphorylation and Membrane Trafficking by Phospholipase C-related Inactive Protein/Protein Phosphatase 1 and 2A Signaling Complex Underlying Brain-derived Neurotrophic Factor-dependent Regulation of GABAergic Inhibition^*

Takashi Kanematsu, Atsushi Yasunaga, Yoshito Mizoguchi¹, Akiko Kuratani², Josef T. Kittler^¶, Jasmina N. Jovanovic^||, Kei Takenaka^**, Keiichi I. Nakayama, Kiyoko Fukami, Tadaomi Takenawa^**, Stephen J. Moss^¶¶, Junichi Nabekura, and Masato Hirata³

From the Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science and Station for Collaborative Research, Kyushu University, Fukuoka 812-8582, Japan, the Department of Developmental Physiology, National Institute for Physiological Science, Okazaki 444-8585, Japan, the ^¶Department of Physiology, University College London, London WC1E 6BT, United Kingdom, the ^||Department of Pharmacology, School of Pharmacy, Brunswick Square, London, WC1N 1AX, United Kingdom, the ^**Department of Biochemistry, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan, the Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan, the Laboratory of Genome and Biosignal, Tokyo University of Pharmacy and Life Science, Tokyo 192-0392, Japan, and the ^¶¶Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Brain-derived neurotrophic factor (BDNF) modulates several distinct aspects of synaptic transmission, including GABAergic transmission. Exposure to BDNF alters properties of GABA_A receptors and induces changes in the expression level at the cell surface. Although phospholipase C-related inactive protein-1 (PRIP-1) plays an important role in GABA_A receptor trafficking and function, its role in BDNF-dependent modulation of these receptors, together with the role of PRIP-2, was investigated using neurons cultured from PRIP double knock-out mice. The BDNF-dependent inhibition of whole cell GABA-evoked currents observed in wild type neurons was not detected in neurons cultured from knock-out mice. Instead, a gradual increase in GABA-evoked currents in these neurons correlated with a gradual increase in phosphorylation of GABA_A receptor 3 subunit in response to BDNF. To characterize the specific role(s) that PRIP plays as components of underlying molecular machinery, we examined the recruitment of protein phosphatase(s) to GABA_A receptors. We demonstrate that PRIP associates with phosphatases as well as with subunits. PRIP was found to colocalize with GABA_A receptor clusters in cultured neurons and with recombinant GABA_A receptors when co-expressed in HEK293 cells. Importantly, a peptide mimicking a domain of PRIP involved in binding to subunits disrupted the co-localization of these proteins in HEK293 cells and potently inhibited the BDNF-mediated attenuation of GABA_A receptor currents in wild type neurons. Together, the results suggest that PRIP plays an important role in BDNF-dependent regulation of GABA_A receptors by mediating the specific association between subunits of these receptors with protein phosphatases.

Received for publication, April 3, 2006 , and in revised form, June 1, 2006.

^* This work was supported by a Grant-in-Aid for Scientific Research from the MEXT of Japan (to T. K., Y. M., A. K., and M. H.) and by funds from the Cooperative Study Program of National Institute for Physiological Sciences (to T. K., J. N., and M. H.), the Epilepsy Research Foundation (to M. H.), the Kato Memorial Bioscience Foundation (to T. K.), the Naito Foundation (to T. K.), and the Takeda Science Foundation (to T. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Japan Society for the Promotion of Science research fellow.

² Japan Society for the Promotion of Science research fellow. Recipient of the Iwadare Scholarship.

³ To whom correspondence should be addressed. Tel.: 81-92-642-6317; Fax: 81-92-642-6322; E-mail: hirata1{at}dent.kyushu-u.ac.jp.

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