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The Journal of Neuroscience, March 28, 2007, 27(13):3445-3455; doi:10.1523/JNEUROSCI.4799-06.2007

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Cellular/Molecular
Biphasic Coupling of Neuronal Nitric Oxide Synthase Phosphorylation to the NMDA Receptor Regulates AMPA Receptor Trafficking and Neuronal Cell Death

Gerald A. Rameau,¹ David S. Tukey,^2,3 Elsa D. Garcin-Hosfield,⁴ Roseann F. Titcombe,^2,3 Charu Misra,² Latika Khatri,² Elizabeth D. Getzoff,⁴ and Edward B. Ziff²

¹Department of Urology, Johns Hopkins School of Medicine, Baltimore, Maryland 21287, ²Department of Biochemistry and ³Graduate Program in Neuroscience and Physiology, New York University School of Medicine, New York, New York 10016, and ⁴Department of Molecular Biology and the Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, California 92037

Correspondence should be addressed to Gerald A. Rameau, Department of Urology, Johns Hopkins School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287. Email: grameau1{at}jhmi.edu

Postsynaptic nitric oxide (NO) production affects synaptic plasticity and neuronal cell death. Ca²⁺ fluxes through the NMDA receptor (NMDAR) stimulate the production of NO by neuronal nitric oxide synthase (nNOS). However, the mechanisms by which nNOS activity is regulated are poorly understood. We evaluated the effect of neuronal stimulation with glutamate on the phosphorylation of nNOS. We show that, in cortical neurons, a low glutamate concentration (30 µM) induces rapid and transient NMDAR-dependent phosphorylation of S1412 by Akt, followed by sustained phosphorylation of S847 by CaMKII (calcium-calmodulin-dependent kinase II). We demonstrate that phosphorylation of S1412 by Akt is necessary for activation of nNOS by the NMDAR. nNOS mutagenesis confirms that these phosphorylations respectively activate and inhibit nNOS and, thus, transiently activate NO production. A constitutively active (S1412D), but not a constitutively repressed (S847D) nNOS mutant elevated surface glutamate receptor 2 levels, demonstrating that these phosphorylations can control AMPA receptor trafficking via NO. Notably, an excitotoxic stimulus (150 µM glutamate) induced S1412, but not S847 phosphorylation, leading to deregulated nNOS activation. S1412D did not kill neurons; however, it enhanced the excitotoxicity of a concomitant glutamate stimulus. We propose a swinging domain model for the regulation of nNOS: S1412 phosphorylation facilitates electron flow within the reductase module of nNOS, increasing nNOS sensitivity to Ca²⁺-calmodulin. These findings suggest a critical role for a kinetically complex and novel series of regulatory nNOS phosphorylations induced by the NMDA receptor for the in vivo control of nNOS.

Key words: neuronal nitric oxide synthase; nNOS; NMDA receptor; AMPA receptor; excitotoxicity; phosphorylation; dephosphorylation

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Received June 16, 2006; revised Jan. 24, 2007; accepted Feb. 8, 2007.

Correspondence should be addressed to Gerald A. Rameau, Department of Urology, Johns Hopkins School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287. Email: grameau1{at}jhmi.edu

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