P2Y nucleotide receptors in the immune system: Signaling by a P2Y2 receptor in U937 monocytes

Abstract

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 P2Y2 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, P2Y2 receptor activation leads to phosphorylation of MKK3 and p38, mitogen‐activated protein kinases. P2Y2 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 short‐term (<30 minutes) agonist treatments, whereas long‐term (>1‐hour) treatments produced sustained desensitization correlating with a decrease in P2Y2 receptor mRNA levels. To investigate the molecular determinants of desensitization, a recombinant P2Y2 receptor was expressed in human astrocytoma cells in which it exhibited agonist‐induced desensitization and sequestration. P2Y2 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 P2Y2 receptor binds specifically to αvβ3 and αvβ5 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 P2Y2 receptor, information that could promote the design of compounds for selective modulation of immune function. Drug Dev. Res. 45:222–228, 1998. © 1998 Wiley‐Liss, Inc.

Ectonucleotidases as Regulators of Purinergic Signaling in Thrombosis, Inflammation, and Immunity

“…The fate of such generated NAD + is controlled by ecto-NADases, and cellular cross-talk that includes CD38 and select forms of ART, such as ART2.2 involved in immune regulation, has been demonstrated (Adriouch et al, 2008; Haag et al, 2007). Later, responses include those more protracted developmental responses, inclusive of cell proliferation, differentiation, and apoptosis (Burnstock & Knight, 2004; Harden et al, 1997; Weisman et al, 1998). …”

Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation

“…Our data therefore indicate that ATP-mediated desensitization of the P2Y1 receptor was solely responsible for the platelet dysfunction in mutant mice. Such desensitization of P2Y-type receptors may limit the physiological effects of specific agonists, and seems mostly dependent on either receptor density or phosphorylation by protein kinases 26 .…”

The role of purinergic signaling in the liver and in transplantation: effects of extracellular nucleotides on hepatic graft vascular injury, rejection and metabolism

“…Over fifteen P2-receptors of different specificities transmit signals from extracellular nucleotides, triggering and modulating vascular and immune cell activation processes, metabolism, nitric oxide (NO) release, adhesion, migration, proliferation and apoptosis (26,27). Since the original cloning of the P2Y2R subtype, at least eight P2YR and seven P2XR subtypes have been cloned and functionally identified.…”

“…Like other members of the G protein coupled receptor family, some P2Y receptors readily undergo agonist-induced desensitization (56). This may involve phosphorylation of the receptor by multiple protein kinases (27). For unclear reasons, P2X-and P2Y-type receptors differ widely with respect to desensitization rates: rapidly desensitizing receptors and/or channels (P2Y1, P2Y2, P2X1 and P2X3) contrast with slow desensitizing receptors such as the P2Y6, P2X2 and P2X7 receptors (the last has proven to be very important in inflammatory reactions); P2X4 is intermediate in this regard (57).…”