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J. Biol. Chem., Vol. 279, Issue 14, 14307-14314, April 2, 2004

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Bidirectional Regulation of Neuronal Nitric-oxide Synthase Phosphorylation at Serine 847 by the N-Methyl-D-aspartate Receptor^*

Gerald A. Rameau, Ling-Yu Chiu, and Edward B. Ziff

From the Howard Hughes Medical Institute, Department of Biochemistry, New York University School of Medicine, New York, New York 10016

At glutamatergic synapses, the scaffolding protein PSD95 links the neuronal isoform of nitric-oxide synthase (nNOS) to the N-methyl-D-aspartate (NMDA) receptor. Phosphorylation of nNOS at serine 847 (Ser⁸⁴⁷) by the calcium-calmodulin protein kinase II (CaMKII) inhibits nNOS activity, possibly by blocking the binding of Ca²⁺-CaM. Here we show that the NMDA mediates a novel bidirectional regulation of Ser⁸⁴⁷ phosphorylation. nNOS phosphorylated at Ser⁸⁴⁷ colocalizes with the NMDA receptor at spines of cultured hippocampal neurons. Treatment of neurons with 5 µM glutamate stimulated CaMKII phosphorylation of nNOS at Ser⁸⁴⁷, whereas excitotoxic concentrations of glutamate, 100 and 500 µM, induced Ser⁸⁴⁷-PO₄ dephosphorylation by protein phosphatase 1. Strong NMDA receptor stimulation was likely to activate nNOS under these conditions because protein nitration to form nitrotyrosine, a marker of nNOS activity, correlated in individual neurons with Ser⁸⁴⁷-PO₄ dephosphorylation. Of particular note, stimulation with low glutamate that increased phosphorylation of nNOS at Ser⁸⁴⁷ could be reversed by subsequent high glutamate treatment which induced dephosphorylation. The reversibility of NMDA receptor-induced phosphorylation at Ser⁸⁴⁷ by different doses of glutamate suggests two mechanisms with opposite effects: 1) a time-dependent negative feedback induced by physiological concentrations of glutamate that limits nNOS activation and precludes the overproduction of NO; and 2) a pathological stimulation by high concentrations of glutamate that leads to unregulated nNOS activation and production of toxic levels of NO. These mechanisms may share pathways, respectively, with NMDA receptor-induced forms of synaptic plasticity and excitotoxicity.

Received for publication, October 8, 2003 , and in revised form, December 22, 2003.

^* This work was supported in part by Grant R01 AG13620 from the NIA, National Institutes of Health, and by pilot project funds from New York University/NIEHS, National Institutes of Health, Grant ES 00260. 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.

Aaron Diamond Foundation postdoctoral research fellow, United Negro College Fund-Merck fellow, and an associate of the Howard Hughes Medical Institute. Supported by National Institutes of Health Training Grant NS 07457-04.

Investigator of the Howard Hughes Medical Institute. To whom correspondence should be addressed: Howard Hughes Medical Institute, Dept. of Biochemistry, New York University School of Medicine, 550 First Ave., New York, NY 10016. Tel.: 212-263-5774; Fax: 212-683-8453; E-mail: edward.ziff{at}med.nyu.edu.

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