{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSLC23A2, which encodes the sodium‐dependent vitamin C transporter type‐2 (SVCT2), is a pivotal mediator of ascorbate uptake that operates in a wide variety of tissues. In the brain, SVCT2 is responsible for the concentrative uptake of ascorbic acid by neurons—an essential step to maintain high antioxidant levels and modulate neuromodulatory processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In the intestine, SVCT2 is localized at the basolateral membrane of enterocytes, thereby functioning in the directed trafficking of vitamin C from the epithelia into the circulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Likewise, endothelial cells express SVCT2, where its activity influences the intracellular redox state in response to inflammatory signals."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In addition, SVCT2 has been found in intracellular compartments such as mitochondria in HEK-293 cells, operating as a low-affinity transporter that is sensitive to the ionic microenvironment."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Expression in placental trophoblasts and first-trimester chorionic villi suggests that SVCT2 plays a crucial role in supplying vitamin C to the developing fetus"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", while in chondrocytes and skeletal muscle cells it facilitates high‐concentration accumulation of ascorbic acid essential for collagen synthesis and oxidative stress defence."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSVCT2 function is dynamically modulated by its local biochemical environment and by cellular signaling mechanisms. Biophysical studies have revealed that its transport cycle is dependent on specific ionic conditions—including a requirement for Ca²⁺/Mg²⁺—and that ascorbic acid itself can cooperatively modify sodium-binding, collectively dictating transport stoichiometry."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " In platelets, changes in ascorbate levels are met with translational regulation of SVCT2, thereby maintaining the redox balance during activation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", and during monocyte-to-macrophage differentiation SVCT2 expression is upregulated in a PKC- and MAPK-dependent manner."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Furthermore, alternative splicing of SLC23A2 can yield a truncated SVCT2 isoform that exerts dominant-negative effects on vitamin C uptake"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", and genetic variants in SLC23A2 are associated with altered risks for spontaneous preterm birth"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "and head and neck cancers."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " Moreover, specific intracellular targeting signals in the N-terminus of SVCT2 are critical for its basolateral and mitochondrial localization"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ", while in breast cancer cells overexpression of a mitochondrial SVCT2 variant correlates with altered vitamin C acquisition strategies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Fiona E Harrison, James M May "}, {"type": "b", "children": [{"type": "t", "text": "Vitamin C function in the brain: vital role of the ascorbate transporter SVCT2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Free Radic Biol Med (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.freeradbiomed.2008.12.018"}], "href": "https://doi.org/10.1016/j.freeradbiomed.2008.12.018"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19162177"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19162177"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "James C Boyer, Christine E Campbell, Wade J Sigurdson, et al. 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