P2RY4 is a G protein-coupled pyrimidinergic receptor that functions as a UTP receptor coupled to phosphatidylinositol-calcium second messenger systems 1. The receptor is activated by UTP and UDP but not ATP or ADP, and mediates phospholipase C-activating signaling that increases cytosolic calcium levels. P2RY4 is expressed on astrocytes in the central nervous system, where its upregulation in epileptic brain lesions correlates with epileptogenesis through activation of intracellular and glio-neuronal signaling pathways 23. Beyond neurological functions, P2RY4 has been identified as a hub gene in several disease contexts. A loss-of-function N178T variant in the second extracellular loop protects against coronary artery disease severity and is associated with improved glucose homeostasis and insulin sensitivity in humans and mice, suggesting P2Y4 antagonists may have therapeutic potential for myocardial infarction and type 2 diabetes 4. P2RY4 expression is dysregulated in hepatocellular carcinoma and irritable bowel syndrome-diarrhea 5617, positioning it as a potential biomarker and therapeutic target in multiple disease states. The receptor's role in mucosal neurotransmission and cellular signaling makes it relevant to gastrointestinal pathobiology.