{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe P2Y2 receptor plays an instrumental role in orchestrating innate immune responses. In neutrophils, ATP released at the leading edge activates P2Y2 receptors in an autocrine manner to amplify chemotactic signals and direct cell migration. In parallel, P2Y2 signaling in monocytes and endothelial cells promotes the secretion of pro‐inflammatory mediators such as IL‑8 and regulates receptor cross‑talk—mechanisms that enhance the recruitment of immune cells during inflammation."}, {"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": "\nWithin the vascular system, activation of the P2Y2 receptor mediates endothelial responses to mechanical forces. For instance, fluid shear stress elicits ATP release that, through P2Y2 receptors, induces intracellular calcium mobilization and nitric oxide production—key steps in maintaining vascular tone and controlling blood pressure. In addition, P2Y2‐mediated signaling at the endothelial barrier contributes to phenotypic modifications that facilitate platelet‐driven tumor cell extravasation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn diverse malignancies, aberrant P2Y2 receptor activation by extracellular ATP or UTP fuels tumor progression. The receptor engages signaling platforms involving Src, mitogen‑activated protein kinases, and epidermal growth factor receptor transactivation to stimulate cell proliferation, migration, and invasion. Through induction of epithelial–mesenchymal transition markers (such as IL‑8, Snail, and modulation of E‑cadherin) and by facilitating inflammasome activation as well as extracellular matrix remodeling (including LOX‐mediated collagen crosslinking), P2Y2 receptor signaling is implicated in metastasis of breast, prostate, ovarian, and liver cancers. Moreover, in certain viral infections like HIV‑1, P2Y2 activation promotes fusion processes that aid viral entry."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "24"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond immunomodulation and tumorigenesis, P2Y2 receptor activity is crucial for tissue homeostasis and repair. In various epithelial systems—including those of the cornea, airway, endometrium, and skin—P2Y2 activation triggers intracellular calcium mobilization and downstream MAPK signaling, which coordinate wound repair and cell regeneration. In bone, P2Y2 receptors contribute to intercellular calcium wave propagation, influencing osteoblast differentiation and communication. These diverse effects underscore the receptor’s broader role in maintaining tissue integrity under physiologic and stress conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "25", "end_ref": "32"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic studies further highlight the clinical relevance of the P2Y2 receptor. Specific non‑synonymous polymorphisms within the P2RY2 gene are linked to variations in blood pressure and hypertension risk. In the central nervous system, altered P2Y2 receptor expression has been associated with neurodegenerative conditions such as Alzheimer’s disease, possibly via effects on neuroinflammation and synaptic maintenance. Post‑translational modifications that govern receptor phosphorylation and desensitization further modulate its signaling output across tissues."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "33", "end_ref": "36"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yu Chen, Ross Corriden, Yoshiaki Inoue, et al. 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