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J. Biol. Chem., Vol. 282, Issue 28, 20075-20087, July 13, 2007

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Fyn-mediated Phosphorylation of NR2B Tyr-1336 Controls Calpain-mediated NR2B Cleavage in Neurons and Heterologous Systems^*

Hai-Yan Wu, Fu-Chun Hsu, Amy J. Gleichman, Isabelle Baconguis, Douglas A. Coulter, and David R. Lynch¹

From the Departments of Pediatrics and Neurology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and the Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104

Cleavage of the intracellular carboxyl terminus of the N-methyl-D-aspartate (NMDA) receptor 2 subunit (NR2) by calpain regulates NMDA receptor function and localization. Here, we show that Fyn-mediated phosphorylation of NR2B controls calpain-mediated NR2B cleavage. In cultured neurons, calpain-mediated NR2B cleavage is significantly attenuated by blocking NR2B phosphorylation of Tyr-1336, but not Tyr-1472, via inhibition of Src family kinase activity or decreasing Fyn levels by small interfering RNA. In HEK cells, mutation of Tyr-1336 eliminates the potentiating effect of Fyn on calpain-mediated NR2B cleavage. The potentiation of NR2B cleavage by Fyn is limited to cell surface receptors and is associated with calpain translocation to plasma membranes during NMDA receptor activation. Finally, reducing full-length NR2B by calpain does not decrease extrasynaptic NMDA receptor function, and truncated NR1/2B receptors similar to those generated by calpain have electrophysiological properties matching those of wild-type receptors. Thus, the Fyn-controlled regulation of NMDA receptor cleavage by calpain may play critical roles in controlling NMDA receptor properties during synaptic plasticity and excitotoxicity.

Received for publication, January 22, 2007 , and in revised form, May 24, 2007.

^* This work was supported by National Institutes of Health Grant NS45986, the Trisomy 21 program and Mental Retardation Research Center of the Children's Hospital of Philadelphia (to D. R. L.), and American Heart Association Grant 0625390U (to H. Y. W.). 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 To whom correspondence should be addressed: Division of Neurology, Children's Hospital of Philadelphia, 502 Abramson Bldg., Philadelphia, PA 19104-4318. Tel.: 215-590-2242; Fax: 215-590-3779; E-mail: lynch{at}pharm.med.upenn.edu.

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