P2Y nucleotide receptors in the immune system: Signaling by a P2Y(2) receptor in U937 monocytes

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 line age, a P2Y(2) receptor subtype activated equipotently by adenosine 5'-triph osphate (ATP) and uridine 5'-triphosphate (UTP) is coupled to phospholipase C and regulates low density lipoprotein uptake, superoxide production, gat ing of calcium channels, and phagocytosis. In U937 monocytes, P2Y(2) recept or activation leads to phosphorylation of MKK3 and p38, mitogen-activated p rotein 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 (<3 0 minutes) agonist treatments, whereas long-term (>1-hour) treatments produ ced sustained desensitization correlating with a decrease in P2Y(2) recepto r 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 s ites for protein kinases were resistant to desensitization and sequestratio n. Other results indicate that an integrin-binding domain, arginine-glycine -aspartate (RGD), in the first extracellular loop of the P2Y(2) receptor bi nds specifically to alpha(v)beta(3) and alpha(v)beta(5) integrins (vitronec tin receptors), an intriguing finding considering the wide distribution of these receptors among immune cells. The RGD domain was necessary for locali zing 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. Drug D ev. Res. 45:222-228, 1998. (C) 1998 Wiley-Liss, Inc.