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J. Biol. Chem., Vol. 282, Issue 12, 9269-9278, March 23, 2007

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A Three Amino Acid Tail Following the TM4 Region of the N-Methyl-D-aspartate Receptor (NR) 2 Subunits Is Sufficient to Overcome Endoplasmic Reticulum Retention of NR1-1a Subunit^*

Wei Yang¹, Chanying Zheng¹, Qilin Song, Xiujuan Yang, Shuang Qiu, Chunqing Liu, Zhong Chen, Shumin Duan, and Jianhong Luo²

From the Department of Neurobiology, Institute for Neuroscience, Zhejiang University School of Medicine, Hangzhou 3100058, China and the Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China

The cytoplasmic C-terminal domains of NR2 subunits have been proposed to modulate the assembly and trafficking of NMDA receptors. However, questions remain concerning which domains in the C terminus of NR2 subunits control the assembly of receptor complexes and how the assembled complexes are selectively trafficked through the various cellular compartments such as endoplasmic reticulum (ER) to the cell surface. In the present study, we found that the three amino acid tail after the TM4 region of NR2 subunits is necessary for surface expression of functional NMDA receptors, while truncations with only two amino acids following the TM4 region (NR22) completely eliminated surface expression of the NMDA receptor on co-expression with NR1-1a in HEK293 cells. FRET (fluorescence resonance energy transfer) analysis showed that these NR22 truncations are able to form homomers and heteromers on co-expression with NR1-1a. Furthermore, when NR22 subunits were cotransfected with either the NR1-4a or NR1-1a_AAA mutant, lacking the ER retention motif (RRR), functional NMDA receptors were detected in the transfected HEK293 cells. Unexpectedly, we found that the replacement of five residues after TM4 with alanines gave results indistinguishable from those of NR2B5 (EHLFY), demonstrating the short tail following the TM4 of NR2 subunits is not sequence-specific-dependent. Taken together, our results show that the C terminus of the NR2 subunits is not necessary for the assembly of NMDA receptor complexes, whereas a three amino acid long cytoplasmic tail following the TM4 of NR2 subunits is sufficient to overcome the ER retention existing in the C terminus of NR1, allowing the assembled NMDA receptors to reach the cell surface.

Received for publication, January 3, 2007 , and in revised form, January 24, 2007.

^* This work was supported in part by the National Basic Research Program of China (No. G2002CB713808), the National Natural Science Foundation of China (30270436, 30470547), and an Outstanding Cross-Century Faculty Grant from the Ministry of Education of China. 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 These authors contributed equally to this work.

² To whom correspondence should be addressed. E-mail: luojianhong{at}zju.edu.cn.

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