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J. Biol. Chem., Vol. 281, Issue 24, 16583-16590, June 16, 2006

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Regulation of NR1/NR2C N-Methyl-D-aspartate (NMDA) Receptors by Phosphorylation^*

Bo-Shiun Chen, Stephanie Braud, John D. Badger, II, John T. R. Isaac, and Katherine W. Roche¹

From the NINDS, National Institutes of Health, Bethesda, Maryland 20892 and the Medical Research Council Centre for Synaptic Plasticity, Department of Anatomy, University of Bristol, Bristol BS8 1TD, United Kingdom

NR2C-containing N-methyl-D-aspartate (NMDA) receptors are highly expressed in cerebellar granule cells where they mediate the majority of current in the adult. NMDA receptors composed of NR1/NR2C exhibit a low conductance and reduced sensitivity to Mg²⁺, compared with the more commonly studied NR2A- and NR2B-containing receptors. Despite these interesting features, very little is known about the regulation of NR2C function. Here we investigate the role of phosphorylation of NR2C in regulating NMDA receptor trafficking and ion channel properties. We identify a phosphorylation site, serine 1244 (Ser¹²⁴⁴), near the extreme COOH terminus of NR2C, which is phosphorylated by both cAMP-dependent protein kinase and protein kinase C. This residue is located adjacent to the consensus PDZ ligand, a region that regulates protein-protein interactions and receptor trafficking in NR2A and NR2B. We show that Ser¹²⁴⁴ on NR2C is phosphorylated in vitro, in heterologous cells, and in neurons. Moreover, we demonstrate for the first time that NR2C interacts with the PSD-95 family of PDZ domain-containing proteins but that phosphorylation of Ser¹²⁴⁴ does not influence this PDZ interaction. Furthermore, Ser¹²⁴⁴ phosphorylation does not regulate surface expression of NR1/NR2C receptors. However, we find that this site does regulate the kinetics of the ion channel: a phosphomimetic mutation at Ser¹²⁴⁴ accelerates both the rise and decay of NMDA-evoked currents in excised patches from HEK-293 cells. Therefore, phosphorylation of Ser¹²⁴⁴ does not regulate trafficking but unexpectedly affects ion channel function, suggesting that phosphorylation of Ser¹²⁴⁴ on NR2C may be important in defining the functional properties of NMDA receptor-mediated currents in the cerebellum.

Received for publication, December 6, 2005 , and in revised form, March 13, 2006.

^* This work was supported by the NINDS/National Institutes of Health Intramural Research Program and the Wellcome Trust (to J. T. R. I.). 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.

This article was selected as a Paper of the Week.

¹ To whom correspondence should be addressed: NINDS, National Institutes of Health, Bldg. 35, Rm. 2C903, Bethesda, MD 20892. Tel.: 301-496-3800; Fax: 301-480-5686; E-mail: rochek{at}ninds.nih.gov.

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