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J. Biol. Chem., Vol. 277, Issue 33, 29753-29759, August 16, 2002

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Peroxynitrite Stimulates L-Arginine Transport System y⁺ in Glial Cells
A POTENTIAL MECHANISM FOR REPLENISHING NEURONAL L-ARGININE^*

Victoria Vega-Agapito^§, Angeles Almeida^¶, Maria Hatzoglou, and Juan P. Bolaños^**

From the  Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, 37007 Salamanca, Spain, ^¶ Unidad de Investigación, Hospital Universitario de Salamanca, 37007 Salamanca, Spain, and the  Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4919

We have reported previously that peroxynitrite stimulates L-arginine release from astrocytes, but the mechanism responsible for such an effect remains elusive. To explore this issue, we studied the regulation of L-[³H]arginine transport by either exogenous or endogenous peroxynitrite in glial cells. A 2-fold peroxynitrite-mediated stimulation of L-arginine release in C6 cells was found to be Na⁺-independent, was prevented by 5 mM L-arginine and, although only in the presence of Na⁺, was blocked by 5 mM L-alanine or L-leucine. Peroxynitrite-mediated stimulation of L-arginine uptake was trans-stimulated by 10 mM L-arginine and was inhibited in a dose-dependent fashion (k_i of ~40 µM) by the system y⁺ inhibitor N-ethylmaleimide in C6 cells. Endogenous production of peroxynitrite in lipopolysaccharide-treated astrocytes triggered an increased L-arginine transport activity without affecting Cat1 L-arginine transporter mRNA levels. However, Western blot analyses of peroxynitrite-treated astrocytes and C6 glial cells revealed a 3-nitrotyrosinated anti-Cat1-immunopositive band, strongly suggesting peroxynitrite-mediated Cat1 nitration. Furthermore, peroxynitrite stimulation of L-arginine release was abolished in fibroblast cells homozygous for a targeted inactivation of the Cat1 gene. Finally, peroxynitrite-triggered L-arginine released from astrocytes was efficiently taken up by neurons in an insert-based co-culture system. These results strongly suggest that peroxynitrite-mediated activation of the Cat1 transporter in glial cells may serve as a mechanism focused to replenish L-arginine in the neighboring neurons.

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