G protein-coupled P2Y nucleotide receptors have been described in cells of the immune system, including neutrophils, monocytes, macrophages, B-and T-lymphocytes, granulocytes, and myeloblasts. In the monocyte/macrophage lineage, a P2Y 2 receptor subtype activated equipotently by adenosine 5′-triphosphate (ATP) and uridine 5′-triphosphate (UTP) is coupled to phospholipase C and regulates low density lipoprotein uptake, superoxide production, gating of calcium channels, and phagocytosis. In U937 monocytes, P2Y 2 receptor activation leads to phosphorylation of MKK3 and p38, mitogen-activated protein kinases. P2Y 2 receptors in U937 monocytes undergo agonist-induced desensitization that decreases the potency and efficacy of subsequent doses of agonist. Cells recover rapidly from desensitization after shortterm (<30 minutes) agonist treatments, whereas long-term (>1-hour) treatments produced sustained desensitization correlating with a decrease in P2Y 2 receptor mRNA levels. To investigate the molecular determinants of desensitization, a recombinant P2Y 2 receptor was expressed in human astrocytoma cells in which it exhibited agonist-induced desensitization and sequestration. P2Y 2 receptors containing C-terminal deletions of potential phosphorylation sites for protein kinases were resistant to desensitization and sequestration. Other results indicate that an integrin-binding domain, arginine-glycine-aspartate (RGD), in the first extracellular loop of the P2Y 2 receptor binds specifically to α v β 3 and α v β 5 integrins (vitronectin receptors), an intriguing finding considering the wide distribution of these receptors among immune cells. The RGD domain was necessary for localizing the receptor to focal adhesion complexes to promote efficient receptor signaling. Finally, positively charged amino acids were identified in the ligand binding site of the P2Y 2 receptor, information that could promote the design of compounds for selective modulation of immune function.