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J. Biol. Chem., Vol. 281, Issue 46, 34859-34869, November 17, 2006

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Neural Cell Adhesion Molecule-associated Polysialic Acid Inhibits NR2B-containing N-Methyl-D-aspartate Receptors and Prevents Glutamate-induced Cell Death^*

Martin S. L. Hammond¹, Catrina Sims¹, Kodeeswaran Parameshwaran, Vishnu Suppiramaniam², Melitta Schachner^¶3, and Alexander Dityatev^||

From the Zentrum für Molekulare Neurobiologie Hamburg and ^||Institut für Neurophysiologie und Pathophysiologie, Universitätsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany, Department of Pharmacal Sciences, Harrison School of Pharmacy, Auburn University, Auburn, Alabama 36849, and ^¶Dalian Medical University, Dalian 116023, China

The neural cell adhesion molecule (NCAM) and its associated glycan polysialic acid play important roles in the development of thenervoussystemandN-methyl-D-aspartate(NMDA)receptor-dependent synaptic plasticity in the adult. Here, we investigated the influence of polysialic acid on NMDA receptor activity. We found that glutamate-elicited NMDA receptor currents in cultured hippocampal neurons were reduced by 30% with the application of polysialic acid or polysialylated NCAM but not by the sialic acid monomer, chondroitin sulfate, or non-polysialylated NCAM. Polysialic acid inhibited NMDA receptor currents elicited by 3 µM glutamate but not by 30 µM glutamate, suggesting that polysialic acid acts as a competitive antagonist, possibly at the glutamate binding site. The polysialic acid induced effects were mimicked and fully occluded by the NR2B subunit specific antagonist, ifenprodil. Recordings from single synaptosomal NMDA receptors reconstituted in lipid bilayers revealed that polysialic acid reduced open probability but not the conductance of NR2B-containing NMDA receptors in a polysialic acid and glutamate concentration-dependent manner. The activity of single NR2B-lacking synaptosomal NMDA receptors was not affected by polysialic acid. Application of polysialic acid to hippocampal cultures reduced excitotoxic cell death induced by low micromolar concentration of glutamate via activation of NR2B-containing NMDA receptors, whereas enzymatic removal of polysialic acid resulted in increased cell death that occluded glutamate-induced excitotoxicity. These observations indicate that the cell adhesion molecule-associated glycan polysialic acid is able to prevent excitotoxicity via inhibition of NR2B subunit-containing NMDA receptors.

Received for publication, March 20, 2006 , and in revised form, August 16, 2006.

^* This work was supported by Deutsche Forschungsgemeinschaft Grant DI 702/5-1,2,3 (to A. D.). 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 may be addressed: Dept. of Pharmacal Sciences, Auburn University, Auburn, AL 36849. Tel.: 334-844-8296; Fax: 334-844-8331; E-mail: suppivd{at}auburn.edu. ³ To whom correspondence may be addressed: Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany. Tel.: 49-40-42803-6246; Fax: 49-89-42803-6248; E-mail: melitta.schachner{at}zmnh.uni-hamburg.de.

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