{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nORAI2 is a pore‐forming subunit of CRAC channels that contributes to store‐operated Ca²⁺ entry and displays unique regulatory and pharmacological features. Studies have shown that when coexpressed with STIM1, ORAI2 substantially increases CRAC current, exhibiting similar Ca²⁺ binding affinities within the selectivity filter as its paralogs, while demonstrating distinct responses to pharmacological agents such as 2‑APB. In addition, variations in the conserved coiled‑coil domains among Orai isoforms suggest that ORAI2, in contrast to ORAI1 and ORAI3, maintains moderate activation under mutations that disrupt STIM1 coupling and mediates fast Ca²⁺‑dependent inactivation through specific C-terminal glutamates."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its fundamental role in Ca²⁺ signaling, ORAI2 is a critical modulator of cellular processes implicated in oncogenesis and other pathologies. In gastric cancer cells, ORAI2 is upregulated in metastatic tissues and promotes tumor formation, cell motility, and invasion via activation of the PI3K/Akt and FAK-mediated MAPK/ERK pathways. In hematological malignancies such as acute myeloid leukemia, ORAI2 is highly expressed and its silencing robustly diminishes store-operated Ca²⁺ entry, proliferation, and migration. Its participation in heteromeric channel complexes is evident in platelets, where ORAI2 associates with STIM proteins to regulate Ca²⁺ influx, and in chondrosarcoma cells where ORAI2 interacts with ORAI1 to fine-tune agonist-induced Ca²⁺ entry. Moreover, in renal epithelial cells, ORAI2 contributes to Ca²⁺-dependent albumin reabsorption, while in oral cancer models both ORAI1 and ORAI2 overexpression correlate with enhanced Ca²⁺ uptake and activation of the Akt/mTOR/NF-κB signaling cascade."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "11"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of neurodegeneration, emerging evidence positions ORAI2 as a key regulator of Ca²⁺ homeostasis with implications for Alzheimer’s disease and glioblastoma. RNA editing events affecting ORAI2 in the brain have been associated with Alzheimer’s dementia and cognitive decline, suggesting that altered ORAI2 function may perturb Ca²⁺ signaling and contribute to amyloid‑β accumulation. In neuroglioma models, modulation of ORAI2 expression alters both the amplitude of store‑operated Ca²⁺ entry and endoplasmic reticulum Ca²⁺ content, thereby influencing amyloid‑β secretion. Furthermore, bioinformatic analyses in glioblastoma underscore the potential of ORAI2 as a critical mediator in tumor progression within the central nervous system."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "14"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Wayne I DeHaven, Jeremy T Smyth, Rebecca R Boyles, et al. 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