Nitric Oxide Modulates Sodium Vitamin C Transporter 2 (SVCT-2) Protein Expression via Protein Kinase G (PKG) and Nuclear Factor-κB (NF-κB)

• Published in: The Journal of biological chemistry 2012-02, Vol.287 (6), p.3860-3872
• Main Authors: Portugal, Camila Cabral, Encarnação, Thaísa Godinho da, Socodato, Renato, Moreira, Sarah Rodrigues, Brudzewsky, Dan, Ambrósio, António Francisco, Paes-de-Carvalho, Roberto
• Format: Article
• Language: English
• Subjects: Animals; Ascorbic Acid; Ascorbic Acid - genetics; Ascorbic Acid - metabolism; Biological Transport, Active - physiology; Cell Proliferation; Chick Embryo; Chickens; Cyclic GMP (cGMP); Cyclic GMP-Dependent Protein Kinases - genetics; Cyclic GMP-Dependent Protein Kinases - metabolism; Gene Expression Regulation - physiology; Guanylate Cyclase (Guanylyl Cyclase); Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurobiology; NF-kappa B - genetics; NF-kappa B - metabolism; NF-κB Transcription Factor; Nitric Oxide; Nitric Oxide - genetics; Nitric Oxide - metabolism; Protein Kinase G (PKG); Retina - cytology; Retina - embryology; Retina - metabolism; Retinal Cultures; Retinal Metabolism; Signal Transduction - physiology; Signaling Pathway; Sodium-Coupled Vitamin C Transporters - genetics; Sodium-Coupled Vitamin C Transporters - metabolism; Vitamin C
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.260166

Ascorbate is an important antioxidant, which also displays important functions in neuronal tissues, including the retina. The retina is responsible for the initial steps of visual processing, which is further refined in cerebral high-order centers. The retina is also a prototypical model for studying physiologic aspects of cells that comprise the nervous system. Of major importance also is the cellular messenger nitric oxide (NO). Previous studies have demonstrated the significance of NO for both survival and proliferation of cultured embryonic retinal cells. Cultured retinal cells express a high-affinity ascorbate transporter, and the release of ascorbate is delicately regulated by ionotropic glutamate receptors. Therefore, we proposed whether there is interplay between the ascorbate transport system and NO signaling pathway in retinal cells. Here we show compelling evidence that ascorbate uptake is tightly controlled by NO and its downstream signaling pathway in culture. NO also modulates the expression of SVCT-2, an effect mediated by cGMP and PKG. Kinetic studies suggest that NO increases the transport capacity for ascorbate, but not the affinity of SVCT-2 for its substrate. Interestingly, NO utilizes the NF-κB pathway, in a PKG-dependent manner, to modulate both SVCT-2 expression and ascorbate uptake. These results demonstrate that NO exerts a fine-tuned control of the availability of ascorbate to cultured retinal cells and strongly reinforces ascorbate as an important bioactive molecule in neuronal tissues. Background: Ascorbate is an important antioxidant that is carried into and out of cells by its high-affinity transporter sodium vitamin C transporter-2 (SVCT-2). Results: Nitric oxide increases SVCT-2 protein levels and ascorbate uptake. Conclusion: Nitric oxide exerts a fine-tuned control of ascorbate availability to retinal cells. Significance: Neuroprotective role of nitric oxide may be achieved by regulating SVCT-2 expression.