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J. Biol. Chem., Vol. 279, Issue 6, 3933-3940, February 6, 2004

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Nitric Oxide Inhibition of ERK1/2 Activity in Cells Expressing Neuronal Nitric-oxide Synthase^*

Kimberly W. Raines, Guan-Liang Cao¶, Supatra Porsuphatana||, Pei Tsai¶, Gerald M. Rosen¶, and Paul Shapiro**

From the Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, the Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, Maryland 21201 and the ^¶Center for Low Frequency EPR for In Vivo Physiology and the ^||Department of Toxicology, Faculty of Pharmaceutical Science, Khon Kaen University, Khon Kaen 40002, Thailand

Neuronal nitric-oxide synthase (nNOS) is a constitutively expressed enzyme responsible for the production of nitric oxide (NO•) from L-arginine and O₂. Nitric oxide is an intra- and intercellular messenger that mediates a diversity of signaling pathways in target cells. In the absence of L-arginine, nNOS has been shown to generate superoxide (). Superoxide, either directly or through its self-dismutation to H₂O₂, is likewise believed to be a cell-signaling agent. Because nNOS can generate NO• and , we examined the activation of cellular signal transduction pathways in nNOS-transfected cells grown in the presence or absence of L-arginine. Spin trapping/EPR spectroscopy confirmed that stimulated nNOS-transfected cells grown in an L-arginine environment secreted NO• into the surrounding milieu. Production of NO• blocked Ca²⁺ ionophore-induced activation of the ERK1/2 through a mechanism involving inhibition of the Ras G-protein and Raf-1 kinase. In contrast, ERK activation was largely unaffected in nNOS-transfected cells grown in L-arginine-free media. Inhibition of nNOS-generated NO• with the competitive NOS inhibitor, N^G-nitro-L-arginine methyl ester, in cells grown in L-arginine restored ERK1/2 activation to levels similar to that found when nNOS was activated in L-arginine-free media. These findings indicate that nNOS can differentially regulate the ERK signal transduction pathway in a manner dependent on the presence of L-arginine and the production of NO•.

Received for publication, May 7, 2003 , and in revised form, November 4, 2003.

^* This work was supported by National Institutes of Health Grant MBRS-IMSD, Grant R25 GM55036 from the Meyerhoff Graduate Fellowship Program, and National Institutes of Health Grants RR-12257 and EB-2034 (to G. M. R.). 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.

^** To whom correspondence should be addressed: University of Maryland School of Pharmacy, 20 North Pine St., Baltimore, MD 21201. Tel.: 410-706-8522; Fax: 410-706-0346; E-mail: pshapiro{at}rx.umaryland.edu.

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