{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTRPV6 is a highly Ca²⁺‐selective epithelial channel that mediates the rate‐limiting step in transcellular calcium absorption in tissues such as the small intestine, kidney, placenta, and even endometrium. Its expression is tightly regulated at the transcriptional level by calciotropic hormones—most notably 1,25‐dihydroxyvitamin D₃—and correlates with the expression of intracellular calcium‐buffering proteins like calbindin as well as basolateral Ca²⁺ pumps. These coordinated expression patterns underscore TRPV6’s central role in maintaining whole‐body calcium homeostasis, bone mineralization, and normal reproductive function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBiophysical and structural studies reveal that TRPV6 exhibits a unique gating mechanism that depends on the ionic milieu. In the presence of extracellular divalent cations, it operates as a Ca²⁺‐selective channel; however, in divalent‐free conditions it even permits monovalent cation permeation. Its activity is modulated by intracellular factors such as Mg²⁺, calmodulin, and phosphatidylinositol 4,5‐bisphosphate (PIP₂), which together determine voltage-dependent gating and Ca²⁺-induced inactivation. High-resolution cryo-electron microscopy and cysteine-scanning mutagenesis have elucidated features such as an aspartate-lined selectivity filter and an unusual conformational transition in the S6 helix that underlies channel opening and closing."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "17"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn several cancer types—including breast, prostate, and pancreatic carcinomas—TRPV6 is markedly up‐regulated, where it contributes to enhanced Ca²⁺ influx that drives cell proliferation, survival, and metastasis. Its expression is subject to modulation by sex steroids (e.g., estrogen, progesterone) and anti‐estrogens (e.g., tamoxifen), indicating its involvement in hormone-dependent tumorigenesis. Moreover, genetic alterations and gene amplifications of TRPV6 have been observed in these malignancies, making it a potential target for therapeutic intervention aimed at curbing oncogenic Ca²⁺ signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "27"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its classical roles in Ca²⁺ uptake, TRPV6 is also involved in processes of cellular differentiation and mechanotransduction. In keratinocytes, for instance, up-regulation of TRPV6 is essential for Ca²⁺-induced differentiation, while in placental trophoblasts, it mediates flow-induced Ca²⁺ influx that triggers phosphorylation events critical for microvilli formation. Moreover, structural determinants such as the third ankyrin repeat not only govern channel assembly but also modulate interactions with other TRP family members (e.g., TRPC1), which in turn influence plasma membrane targeting and channel function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "28", "end_ref": "31"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn certain immune cells, there is evidence linking TRPV6 to store-operated and receptor-activated Ca²⁺ entry mechanisms, although its precise contribution relative to classical CRAC channels remains a subject of debate. Studies in mast cells and T-lymphocytes indicate that while TRPV6 can generate Ca²⁺ entry currents under specific conditions, its activity is distinct from or only a partial component of the endogenous store-operated Ca²⁺ influx pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "32"}, {"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEvolutionary analyses have revealed that the TRPV6 gene has been subjected to recent positive selection in non-African populations. Specific haplotypes defined by non-synonymous polymorphisms suggest that selection may have favored variants with modified functional properties, potentially altering calcium transport efficiency and influencing disease susceptibility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "33"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the human reproductive tract, particularly within the endometrium, TRPV6 helps regulate local calcium homeostasis, which is thought to be critical for proper uterine function and embryo implantation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "35"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNotably, TRPV6 is also permeable to other divalent cations such as cadmium and zinc, thereby potentially mediating the uptake of toxic heavy metals under conditions of low extracellular calcium. This property may have implications for toxicology and metal homeostasis in epithelial tissues."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "36"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "N F Barley, A Howard, D O'Callaghan, et al. 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