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The Journal of Neuroscience, April 5, 2006, 26(14):3626-3633; doi:10.1523/JNEUROSCI.4183-05.2006

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Cellular/Molecular
Membrane-Proximal Region of Glutamate Receptor 2 Subunit Is Critical for Long-Term Depression and Interaction with Protein Interacting with C Kinase 1 in a Cerebellar Purkinje Neuron

Satoshi Yawata,^1,2 Hiroshi Tsuchida,¹ Mineko Kengaku,^1,2,3 and Tomoo Hirano^1,2

¹Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan, ²Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Kawaguchi, Saitama 332-0012, Japan, and ³Laboratory for Neural Cell Polarity, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan

Correspondence should be addressed to Tomoo Hirano, Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan. Email: thirano{at}neurosci.biophys.kyoto-u.ac.jp

The glutamate receptor 2 subunit (GluR2) is selectively expressed in cerebellar Purkinje neurons (PNs) and is involved in the long-term depression (LTD). However, little is known about the mechanism of its action. Acute expression of the wild-type GluR2 in the GluR2-deficient PN rescued the induction of LTD, suggesting the direct role of GluR2 in LTD. To identify the critical region of GluR2 necessary for LTD, we constructed and expressed various mutant GluR2 proteins in the GluR2-deficient PNs. The mutant GluR2 possessing the membrane-proximal 21 aa residues in the C-terminal cytoplasmic region rescued the induction of LTD, whereas the mutant with membrane-proximal 13 aa failed. In addition, overexpression of 865871 aa of GluR2 (corresponding to membrane-proximal 14–20 aa) fused to EGFP (enhanced green fluorescent protein) suppressed LTD in a wild-type PN. These results suggest that 865871 aa of GluR2 play an essential role in LTD. We next identified protein interacting with C kinase 1 (PICK1) as a molecule interacting with the membrane-proximal C-terminal region of GluR2 by yeast two-hybrid screening. PICK1 plays an essential role in LTD. It colocalized with GluR2 at spines of PNs, and immunoprecipitation assays showed that GluR2 bound to PICK1 mainly through 865–871 aa. These results indicate that 865–871 aa of GluR2 are essential for both LTD and interaction with PICK1, and suggest that interaction between GluR2 and PICK1 might be critical for the induction of LTD.

Key words: Purkinje neuron; cerebellum; LTD; glutamate receptor; PICK1; parallel fiber

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Received Oct. 1, 2005; revised Feb. 8, 2006; accepted Feb. 15, 2006.

Correspondence should be addressed to Tomoo Hirano, Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan. Email: thirano{at}neurosci.biophys.kyoto-u.ac.jp

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