{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSLC8A2, also known as the Na⁺/Ca²⁺ exchanger isoform NCX2, plays an integral role in regulating intracellular Ca²⁺ homeostasis in the brain. In synaptic terminals, NCX2 is dynamically modulated under pathological conditions; for example, studies in Alzheimer’s disease have shown that NCX2‐positive nerve terminals are increased and co‐localize with amyloid‐β, suggesting an involvement in the neuronal response to neurodegeneration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMolecular studies have further elucidated mechanisms that regulate NCX2 activity. Using the large regulatory cytoplasmic loop of NCX2 as bait, interactions with members of the 14-3-3 protein family were identified, and such interactions were shown to reduce exchanger activity, thereby influencing Ca²⁺ clearance and cellular calcium signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn neuronal mitochondria, NCX2, along with NCX3, contributes to the extrusion of Ca²⁺ from these organelles. Inhibition of NCX2 function has been demonstrated to reduce mitochondrial Ca²⁺ efflux in dopaminergic neurons, indicating that NCX2 helps to protect cells against Ca²⁺ overload."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, in models of neuromuscular degeneration such as spinal muscular atrophy, modulation of NCX2 expression by miR-206 was found to be neuroprotective. Upregulation of miR-206 led to decreased levels of NCX2, suggesting that fine-tuning NCX2’s activity may help to mediate Ca²⁺-dependent regenerative processes at neuromuscular junctions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNotably, in the context of gliomas, SLC8A2 expression is highly specific to the normal brain and is markedly reduced or absent in tumor tissue. Genetic studies have identified loss of heterozygosity at the NCX2/SLC8A2 locus in gliomas, and functional analyses in glioblastoma models demonstrate that restoration of SLC8A2 expression suppresses tumorigenicity by impairing cell invasion, migration, and angiogenesis. These tumor-suppressive effects are mediated by alterations in intracellular Ca²⁺ dynamics and downstream signaling pathways—including inhibition of ERK1/2/NF‐κB and HIF-1α signaling and reactivation of p53 and PTEN pathways."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditionally, epigenetic studies in the setting of anti-tuberculosis drug-induced liver injury have implicated differential DNA methylation near the SLC8A2 gene region as a factor affecting cellular responses to stress, further underscoring the broader impact of SLC8A2 on Ca²⁺-dependent cellular functions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Sophie Sokolow, Sanh H Luu, Alison J Headley, et al. 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