P2Y₂ Receptor Signaling in Health and Disease

P2Y₂ receptors are a subclass of G protein-coupled receptors activated by the extracellular nucleotides ATP and UTP. These receptors are widely expressed in multiple tissues-including the brain, lungs, heart, and kidneys-and play pivotal roles in inflammation, wound healing, and cell migration. Through coupling with various G proteins, P2Y₂ receptors initiate diverse intracellular signaling pathways that mediate calcium mobilization, cytokine release, and cytoskeletal reorganization. Recent studies highlight their dual roles in health and disease. In physiological contexts, P2Y₂ receptors contribute to immune modulation and tissue repair. In pathological conditions, they are implicated in Alzheimer's disease by promoting non-amyloidogenic processing of amyloid precursor protein and in dry eye disease by enhancing mucin secretion while modulating ocular inflammation. They also influence chloride secretion and mucosal hydration in cystic fibrosis and contribute to inflammatory regulation and epithelial repair in inflammatory bowel disease. Additionally, P2Y₂ receptors modulate breast cancer progression by regulating cell adhesion, migration, and matrix remodeling. Their involvement in blood pressure regulation via epithelial sodium channel modulation and their facilitative role in HIV-1 entry further underscore their clinical significance. These multifaceted functions position P2Y₂ receptors as promising therapeutic targets for diverse diseases, warranting further investigation for translational applications.