MEMBRANE TRANSPORT STRUCTURE FUNCTION AND BIOGENESIS
Sustained Nitric Oxide Production in Macrophages Requires the Arginine Transporter CAT2*

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The aberrant production of nitric oxide (NO) contributes to the pathogenesis of diseases as diverse as cancer and arthritis. Sustained NO production via the inducible enzyme, nitric-oxide synthase 2 (NOS2), requires extracellular arginine uptake. Three closely related cationic amino acid transporter genes (Cat1–3) encode the transporters that mediate most arginine uptake in mammalian cells. Because CAT2 is induced coordinately with NOS2 in numerous cell types, we investigated a possible role for CAT2-mediated arginine transport in regulating NO production. The complexity of arginine transport systems and their biochemically similar transport properties called for a genetic approach to determine the role of CAT2. CAT2-deficient mice were generated and found to be healthy and fertile in contrast toCat1 −/− animals. Analysis of cytokine-activated macrophages from Cat2 −/−mice revealed a 92% reduction in NO production and a 95% reduction inl-Arg uptake. The reduction in NO production was not due to differences in NOS2 protein expression, NOS2 activity, or intracellularl-arginine content. In conclusion, our results show that sustained abundant NO synthesis by macrophages requires arginine transport via the CAT2 transporter.

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Published, JBC Papers in Press, February 16, 2001, DOI 10.1074/jbc.M010030200

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This work was supported by the Susan G. Komen Breast Cancer Foundation, American Institute of Cancer Research Grant 9724, National Institutes of Health Grant CA81376, and the California Breast Cancer Research Program. Support for early phases of this study was provided by the UCSD Academic Senate and the California Research Coordinating Committee.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Susan G. Komen Breast Cancer Research Foundation Postdoctoral Fellow.

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Howard Hughes Medical Institute Predoctoral Fellow.