<scp>SVCT2</scp> transporter expression is post‐natally induced in cortical neurons and its function is regulated by its short isoform

Salazar, Katterine; Cerda, Gustavo A.; Martínez, Fernando Martínez; Sarmiento, José; González, Carlos B.; Rodríguez, Federico; García-Robles, María De Los Ángeles; Tapia, Juan Carlos; Cifuentes, Manuel; Nualart, Francisco

doi:10.1111/jnc.12793

Cited by 23 publications

(37 citation statements)

References 46 publications

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“…It has been shown to negatively regulate the function of the full length transporter by changing its affinity constant via hetero-oligomerization in human embryonic kidney 239T cells and mouse neuronal cells (54). This isoform also had the ability to partially inhibit SVCT1 (54, 55). …”

Section: Sodium-dependent Vitamin C Transportermentioning

confidence: 98%

Vitamin C Transporters in Cancer: Current Understanding and Gaps in Knowledge

2017

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Sufficient uptake and whole body distribution of vitamin C (ascorbate) is essential for many biochemical processes, including some that are vital for tumor growth and spread. Uptake of ascorbate into cancer cells is modulated by availability, tumor blood flow, tissue diffusion parameters, and ascorbate transport proteins. Uptake into cells is mediated by two families of transport proteins, namely, the solute carrier gene family 23, consisting of sodium-dependent vitamin C transporters (SVCTs) 1 and 2, and the SLC2 family of glucose transporters (GLUTs). GLUTs transport the oxidized form of the vitamin, dehydroascorbate (DHA), which is present at negligible to low physiological levels. SVCT1 and 2 are capable of accumulating ascorbate against a concentration gradient from micromolar concentrations outside to millimolar levels inside of cells. Investigating the expression and regulation of SVCTs in cancer has only recently started to be included in studies focused on the role of ascorbate in tumor formation, progression, and response to therapy. This review gives an overview of the current, limited knowledge of ascorbate transport across membranes, as well as tissue distribution, gene expression, and the relevance of SVCTs in cancer. As tumor ascorbate accumulation may play a role in the anticancer activity of high dose ascorbate treatment, further research into ascorbate transport in cancer tissue is vital.

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Section: Sodium-dependent Vitamin C Transportermentioning

confidence: 98%

Vitamin C Transporters in Cancer: Current Understanding and Gaps in Knowledge

2017

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“…These findings indicate that SVCT2 is induced during cell arborization and synaptic maturation of deep neurons in the brain cortex. We also identified the expression of a short isoform of SVCT2 (SVCT2sh), which is unable to transport AA and regulate the functional capacity of the active transporter [1]. This finding and its biological consequence in the postnatal brain will be discussed in the following section.…”

Section: Expression and Polarization Of Svct2 During Brain Developmentmentioning

confidence: 99%

“…SVCT2sh was initially thought to be a possible dominant negative of SVCT2 through protein-protein interaction [28]. However, Forster resonance energy transfer (FRET) studies, a decade later using SVCT2-CFP Vitamin Cand SVCT2sh-YFP in the neural linage cell line, N2a [1], showed that the proteins interact at both the intracellular space and the cell membrane. The functional consequence of the interaction reduces the affinity of SVCT2 for its substrate, AA, in neuronal cells, suggesting that SVCT2 activity and intracellular concentrations of AA are tightly modulated during postnatal development in order to generate a precise physiological intracellular dose of AA to trigger the neuronal differentiation and synaptic maturation in a particular period of development.…”

Section: Regulation Of Svct2-mediated Vitamin C Uptake In Neurons By mentioning

confidence: 99%

“…Many studies indicate that SVCT2 is a transporter that is preferentially expressed in neurons from different areas in the adult brain, such as the cortex, hippocampus, hypothalamus, and cerebellar precursors [1,[7][8][9][10][11]. SVCT2 mediates uptake of AA, an important molecule for antioxidant defense and general metabolic needs of neurons.…”

Section: Distribution and Function Of Svct2 In The Adult Brainmentioning

confidence: 99%

“…At physiological pH, the reduced form of vitamin C, ascorbic acid (AA), predominates and is specifically incorporated by neurons through isoform 2 of the cotransporter of sodium and ascorbate (SVCT2) [1]. Once AA loses its protons, it is oxidized into dehydroascorbic acid (DHA), which diffuses among nervous cells through the facilitative glucose transporters, GLUT1 and GLUT3 [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

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Vitamin C Transporter (SVCT2) Distribution in Developing and Adult Brains

Ferrada¹,

Salazar²,

Santander³

2017

Vitamin C

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Vitamin C is the major antioxidant molecule in the central nervous system (CNS), reaching concentrations of 10 mM in neurons and 400 μM in the cerebrospinal fluid (CSF). Uptake of vitamin C by brain cells is performed through the co-transporter of ascorbic acid and sodium isoform 2, SVCT2, which is expressed in cells from the choroid plexus, neurons, oligodendrocytes, and ependymal cells. SVCT2 expression has also been described in cells at the neurogenic niche, specifically in proliferative type C cells. In this chapter, we will describe recently published studies of SVCT2 expression during brain development and define its polarization in cells from the radial glia (neuronal precursors within the CNS) and vitamin C-mediated effects in regulating genes associated with the maintenance of CNS stem cell pluripotency. We will discuss the differential biological effect that vitamin C generates in neurons versus astrocytes and how the oxidized form of vitamin C, dehydroascorbic acid (DHA), produced by neurons in conditions of oxidative stress must leave this cell to be incorporated by astrocytes. In this context, we will discuss recent literature, which shows that DHA regulates glycolytic metabolism in neurons. In parallel, we will analyze vitamin C recycling by astrocytes, which reduce DHA into ascorbic acid (AA), increasing the antioxidant potential of the brain. Data discussed in this chapter will provide an updated view of SVCT2 distribution in the brain and will also describe how vitamin C recycling participates in normal or pathological brain function.

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Ascorbic acid and its transporterSVCT2, affect radial glia cells differentiation in postnatal stages

Saldivia,

Salazar,

Cifuentes

et al. 2024

Glia

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Radial glia (RG) cells generate neurons and glial cells that make up the cerebral cortex. Both in rodents and humans, these stem cells remain for a specific time after birth, named late radial glia (lRG). The knowledge of lRG and molecules that may be involved in their differentiation is based on very limited data. We analyzed whether ascorbic acid (AA) and its transporter SVCT2, are involved in lRG cells differentiation. We demonstrated that lRG cells are highly present between the first and fourth postnatal days. Anatomical characterization of lRG cells, revealed that lRG cells maintained their bipolar morphology and stem‐like character. When lRG cells were labeled with adenovirus‐eGFP at 1 postnatal day, we detected that some cells display an obvious migratory neuronal phenotype, suggesting that lRG cells continue generating neurons postnatally. Moreover, we demonstrated that SVCT2 was apically polarized in lRG cells. In vitro studies using the transgenic mice SVCT2+/− and SVCT2tg (SVCT2‐overexpressing mouse), showed that decreased SVCT2 levels led to accelerated differentiation into astrocytes, whereas both AA treatment and elevated SVCT2 expression maintain the lRG cells in an undifferentiated state. In vivo overexpression of SVCT2 in lRG cells generated cells with a rounded morphology that were migratory and positive for proliferation and neuronal markers. We also examined mediators that can be involved in AA/SVCT2‐modulated signaling pathways, determining that GSK3‐β through AKT, mTORC2, and PDK1 is active in brains with high levels of SVCT2/AA. Our data provide new insights into the role of AA and SVCT2 in late RG cells.

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SVCT2 transporter expression is post‐natally induced in cortical neurons and its function is regulated by its short isoform

Cited by 23 publications

References 46 publications

Vitamin C Transporters in Cancer: Current Understanding and Gaps in Knowledge

Vitamin C Transporters in Cancer: Current Understanding and Gaps in Knowledge

Vitamin C Transporter (SVCT2) Distribution in Developing and Adult Brains

Ascorbic acid and its transporterSVCT2, affect radial glia cells differentiation in postnatal stages

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