Vitamin C modulates glutamate transport and NMDA receptor function in the retina. Issue 4 (14th December 2017)

• Record Type: Journal Article
• Authors: Domith, Ivan; Socodato, Renato; Portugal, Camila C.; Munis, Andressa F.; Duarte‐Silva, Aline T.; Paes‐de‐Carvalho, Roberto
• Is Part Of: Journal of neurochemistry. Volume 144:Issue 4(2018)
• Page Start: 408
• Page End: 420
• Publication Date: 2017-12-14
• Subjects: ascorbate -- CREB -- d‐aspartate uptake -- dehydroascorbate -- purified and mixed retinal cultures; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.14260
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: Vitamin C (in the reduced form ascorbate or in the oxidized form dehydroascorbate) is implicated in signaling events throughout the central nervous system (CNS). In the retina, a high‐affinity transport system for ascorbate has been described and glutamatergic signaling has been reported to control ascorbate release. Here, we investigated the modulatory role played by vitamin C upon glutamate uptake and N ‐methyl‐d ‐aspartate (NMDA) receptor activation in cultured retinal cells or in intact retinal tissue using biochemical and imaging techniques. We show that both forms of vitamin C, ascorbate or dehydroascorbate, promote an accumulation of extracellular glutamate by a mechanism involving the inhibition of glutamate uptake. This inhibition correlates with the finding that ascorbate promotes a decrease in cell surface levels of the neuronal glutamate transporter excitatory amino acid transporter 3 in retinal neuronal cultures. Interestingly, vitamin C is prone to increase the activity of NMDA receptors but also promotes a decrease in glutamate‐stimulated [ 3 H] MK801 binding and decreases cell membrane content of NMDA receptor glutamate ionotropic receptor subunit 1 (GluN1) subunits. Both compounds were also able to increase cAMP response element‐binding protein phosphorylation in neuronal nuclei in a glutamate receptor and calcium/calmodulin kinase‐dependent manner. Moreover, the effect of ascorbate is not blocked by sulfinpyrazone and then does not depend on its uptake by retinal cells. Overall, these data indicate a novel molecular and functional target for vitamin C impacting on glutamate signaling in retinal neurons. Abstract : We propose that ascorbate or dehydroascorbate promotes the internalization of excitatory aminoacid transporter type 3 (EAAT3) and thereby decreases glutamate uptake by retinal neurons and promotes the accumulation of extracellular glutamate. This accumulated glutamate is then able to stimulate N ‐methyl‐d ‐aspartate (NMDA) and/or AMPA/kainate receptors and activate calcium‐dependent signaling pathways leading to cAMP response element‐binding protein (CREB) phosphorylation.