Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Nucleotide Receptor P2Y

  • Didier Communi
  • Bernard Robaye
  • Jean-Marie Boeynaems
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_198

Synonyms

Historical Background

Signaling by extracellular ATP was first reported in 1929 (Drury and Szent-Györgyi 1929). Subdivision of purinergic receptors between P1 (adenosine) and P2 (ATP, ADP) was proposed in 1978 (Burnstock 1978), and further subdivision of P2 receptors between P2Y and P2X was made in 1985 (Burnstock and Kennedy 1985). The P2Y1 and P2Y2 receptors were the first P2Y receptors to be cloned in 1993 (Webb et al. 1993; Lustig et al. 1993).

Release of Nucleotides in the Extracellular Fluids

Although nucleotides, such as ATP and UTP, are mainly intracellular, they are released in the extracellular fluids by various mechanisms. One of them is cell damage: both necrotic and apoptotic cells release ATP and other nucleotides that thus constitute “danger signals” or DAMP (damage-associated molecular pattern) (Elliott et al. 2009). But they can also be released without cell lysis by specific mechanisms: exocytosis of secretory granules, vesicular transport, and membrane channels, such as ABC transporters, pannexins, and connexins (Abbracchio et al. 2006). Nucleotides are released by exocytosis during platelet aggregation and synaptic transmission. They are also released in response to various types of stress: mechanical stimulation (stretch, shear stress), hypoxia, or pathogen invasion.

Extracellular nucleotides are rapidly degraded by a variety of ectonucleotidases such as the ENTDPases that degrade ATP into ADP and ADP into AMP, and 5′-nucleotidase that converts AMP into adenosine (Abbracchio et al. 2006).

Signaling by extracellular nucleotides is mediated by two families of receptors: metabotropic G protein–coupled P2Y receptors and ionotropic P2X receptors.

Structure and Signaling Properties of P2Y Receptors

The P2Y family is composed of eight members encoded by distinct genes that can be subdivided into two groups based on their coupling to specific G proteins, as well as structural features (Abbracchio et al. 2006).

Whereas the P2X receptors are all receptors for ATP, the various P2Y receptors differ by their selectivity for distinct nucleotides (Table 1). P2Y11 is primarily an ATP receptor, whereas P2Y1, P2Y12, and P2Y13 are ADP receptors. P2Y4 and P2Y6 are pyrimidinergic receptors activated by UTP and UDP, respectively. P2Y2 is a dual ATP and UTP receptor. P2Y14 is a receptor for UDP-glucose and other nucleotide sugars as well as for UDP itself.
Nucleotide Receptor P2Y, Table 1

Properties of P2Y receptors

Group

Receptor

Chromosome

Agonist

G protein

(human)

(human)

A

P2Y1

3q24–25

ADP

Gq

P2Y2

11q13.5

ATP = UTP

Gq (+ Gi)

P2Y4

Xq13

UTP

Gq (+ Gi)

P2Y6

11q13.5

UDP

Gq

P2Y11

19p31

ATP

Gq + Gs

B

P2Y12

3q21–25

ADP

Gi

P2Y13

3q24–25

ADP

Gi

P2Y14

3q24–25

UDP-glucose

Gi

UDP

Comparisons of the structural characteristics and functionally important amino acid residues within the family have been performed using mutagenesis and modeling (Abbracchio et al. 2006). Conserved cationic residues that interact with the negatively charged phosphate groups have been identified in transmembrane domains 3, 6, and 7. The 8 P2Y receptors have a H-X-X-R/K motif in TM6. The P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11 receptors share a Y-Q/K-X-X-R motif in TM7, whereas another motif, K-E-X-X-L., is found in P2Y12, P2Y13, and P2Y14. This last motif is not specific for P2Y receptors since it is also found in GPR87, a lysophosphatidic acid receptor.

The P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11 receptors couple mainly to Gq and the P2Y12, P2Y13, and P2Y14 receptors couple to Gi (Table 1). This coupling has been demonstrated directly in reconstitution experiments: ADP-activated GTP hydrolysis in vesicles containing either P2Y1 and Gαq or P2Y12 and Gαi2 (Waldo and Harden 2004). However, the dichotomy between Gq- and Gi-coupled P2Y receptors is an oversimplification. Indeed, the P2Y11 receptor has the unique property to couple through both Gq and Gs. It is also unique by its late appearance during evolution since no P2Y11 gene can be identified in the genome of rodents (Communi et al. 2001a). Furthermore, the P2Y2 and P2Y4 receptors are also coupled to Gi, as shown interalia by a sensitivity of the responses mediated by those receptors to inhibition by pertussis toxin.

There is limited evidence for non-G-protein-mediated signaling by P2Y receptors. In particular, the P2Y2 receptor has been shown to transactivate the VEGF receptor-2, by a mechanism involving the binding of  Src tyrosine kinase to SH3 binding sites in the C-terminal domain of P2Y2 (Seye et al. 2004).

The pharmacology of some P2Y receptors exhibits species differences: while the human P2Y4 is a UTP receptor, the rat and mouse P2Y4 receptors are activated equipotently by ATP and UTP.

The missing numbers in the classification represent either nonmammalian orthologs or receptors having some sequence homology to P2Y receptors, but for which there is no functional evidence of responsiveness to nucleotides.

Primary references are as follows: P2Y1 (Webb et al. 1993), P2Y2 (Lustig et al. 1993), P2Y4 (Communi et al. 1995), P2Y6 (Communi et al. 1996), P2Y11 (Communi et al. 1997), P2Y12 (Hollopeter et al. 2001), P2Y13 (Communi et al. 2001b), and P2Y14 (Chambers et al. 2000).

Functions of P2Y Receptors

Gene silencing techniques have been instrumental in establishing the function of P2Y receptors (Table 2). ADP released from platelet dense granules amplifies platelet aggregation. This action requires the cooperation between two P2Y receptors: P2Y1 and P2Y12 (Fig. 1). P2Y1 is involved in the initial platelet shape change and transient aggregation, while P2Y12 is responsible for sustained aggregation and secretion. Both P2Y1−/− and P2Y12−/− mice show defective platelet aggregation ex vivo, increased bleeding time, and resistance to thrombosis (Leon et al. 1999; André et al. 2003). The only P2Y receptor ligands currently used as medicinal products are the thienopyridine antagonists of the P2Y12 receptor, ticlopidine, clopidogrel, and prasugrel, which are used as antithrombotic agents.
Nucleotide Receptor P2Y, Table 2

Effects of P2Y gene silencing

Receptor

Gene silencing method

Consequence of gene silencing

P2Y1

Knockout mice

Inhibition of platelet aggregation and resistance to thromboembolism

Smaller atherosclerotic lesions

P2Y2

Knockout mice

Decreased neutrophil and monocyte/macrophage chemotaxis

Decreased infiltration of eosinophils in asthmatic airways

Abolition of ATP-induced Cl secretion in airways and intestinal tract

P2Y4

Knockout mice

Microcardia phenotype related to defective cardiac angiogenesis

Protection against cardiac ischemia

Abolition of ATP-induced Cl secretion in the gut

P2Y6

Knockout mice

Antisense

Cardiac hypertrophy

Reduced vascular inflammation

Decreased microglial phagocytosis

siRNA

Decreased pressure overload-induced cardiac fibrosis

P2Y12

Knockout mice

Inhibition of platelet aggregation and resistance to thromboembolism

Decreased microglial migration

P2Y13

Knockout mice

Decreased differentiation of bone marrow stromal cells into osteoblasts

Reduced bone turnover

Decreased reverse cholesterol transport

Nucleotide Receptor P2Y, Fig. 1

Cooperation between P2Y1 and P2Y12 receptors in platelet aggregation. Activation of the P2Y1 receptor by ADP induces a shape change of platelets and their transient aggregation, while its stimulatory effect on P2Y12 induces a stable aggregation and potentiates the secretion of dense granules content

ATP and UTP stimulate the secretion of chloride by epithelial cells through a channel distinct from Cystic Fibrosis Transmembrane Regulator (CFTR) (Fig. 2). Studies of knockout mice have demonstrated that this action is mediated by the P2Y2 receptor in the airways (Cressman et al. 1999) and by P2Y4 in the gut (Robaye et al. 2003). The P2Y2 agonist denufosol was developed for the treatment of cystic fibrosis, but Phase 3 trials ended up in failure (Ratjen et al. 2012)
Nucleotide Receptor P2Y, Fig. 2

Role of the P2Y2 receptor in the regulation of the airways mucociliary escalator. Activation of the P2Y2 receptor by ATP stimulates the three components of this escalator: mucus secretion, mucus hydration, and mucus mobilization by ciliary activity. Mucus hydration results from Cl secretion which is mediated either by Cystic Fibrosis Transmembrane Regulator (CFTR) or Outwardly rectifying chloride channels (ORCC) that are opened by an increase in [Ca2+]i in response to ATP

Multiple P2Y receptors are expressed in the heart: P2Y2 and P2Y6 receptors on cardiomyocytes and P2Y4 on microvascular endothelial cells. Nucleotides are released from cardiomyocytes in response to mechanical stretch or ischemia. Both P2Y2 and P2Y4 nucleotide receptors are involved in cardioprotection through distinct mechanisms. Administration of UTP to rats reduces infarct size through activation of P2Y2 receptors and protects rat cardiomyocytes against hypoxic stress (Cohen et al. 2011). Loss of mouse P2Y4 receptor is associated with a protection against infarction and reduction of cardiac inflammation, permeability, and fibrosis (Horckmans et al. 2015). The P2Y4 receptor is also involved in postnatal cardiac development (Horckmans et al. 2012a) and exercise tolerance (Horckmans et al. 2012b). The use of siRNA revealed that the P2Y6 receptor plays a role in cardiac fibrosis resulting from pressure overload (Nishida et al. 2008). Recently, loss of P2Y6 was associated with a macrocardia phenotype and amplified pathological cardiac hypertrophy induced after isoproterenol injection (Clouet et al. 2016).

Interestingly, P2Y4 receptor was reported as a potential pivotal regulator in osteogenic and adipogenic differentiation of human mesenchymal stem cells (Ciciarello et al. 2013). P2Y13 plays also a role in the balance of osteoblast and adipogenic differentiation of bone marrow progenitors (Biver et al. 2013), which may explain the reduced bone turn-over in P2Y13−/− mice (Wang et al. 2012).

Multiple P2Y receptors might play a role in the development of atherosclerotic lesions, independently from their role in platelet activation. Aortic lesions were smaller in double ApoE/P2Y1 knockout mice than in ApoE−/− mice (Hechler et al. 2008). This difference was unrelated to the role of P2Y1 in platelet activation since it was unaffected by bone marrow transplantation from P2Y1 wild-type mice, indicating the role of P2Y1 in nonhematopoietic-derived cells, most likely endothelial cells. On the other hand, the P2Y13 receptor plays a role in the reverse cholesterol transport, at the level of hepatocytes. It has indeed been shown that HDL Apo A-I activates an ecto-ATPase that generates ADP from ATP on the surface of hepatocytes. ADP then stimulates the endocytosis of HDL particles via the activation of P2Y13 receptors, as demonstrated by the use of siRNA (Jacquet et al. 2005). Endocytosis of HDL and biliary lipid secretion are decreased in P2Y13−/− mice (Fabre et al. 2010).

P2Y receptors are involved at various steps in the inflammatory process (Fig. 3). ATP released from neutrophils amplifies their attraction by chemotactic signals, and its release from apoptotic cells constitutes a “find-me signal” for monocytes/macrophages (Chen et al. 2006; Elliott et al. 2009). In a murine model of asthma, the infiltration of esosinophils in the airways involves the P2Y2-mediated expression of Vascular Cell Adhesion Molecule-1 (VCAM-1) on lung endothelial cells (Vanderstocken et al. 2010). Expression of the P2Y6 receptor on endothelial cells is increased during vascular inflammation that was reduced in P2Y6−/− mice (Riegel et al. 2011). P2Y receptors are also involved in adaptive immunity. In particular, ATP induces via the P2Y11 receptor the semimaturation of human monocyte-derived dendritic cells, characterized by the upregulation of co-stimulatory molecules and the inhibition of IL-12 secretion, resulting in an enhanced ability to induce Th2 differentiation of T lymphocytes (Wilkin et al. 2001). Moreover, ATP confers tolerogenic and tumorigenic properties to dendritic cells (Marteau et al. 2005; Bles et al. 2010).
Nucleotide Receptor P2Y, Fig. 3

Role of P2Y receptors in various immune cells. The P2Y2 receptor plays a role in the tissue infiltration of eosinophils and the chemotaxis of neutrophils and monocytes. The P2Y11 receptor mediates the semimaturation of dendritic cells that favors Th2 differentiation or tolerance

Microglia from P2Y12−/− mice are unable to polarize, migrate, or extend processes toward ADP, and in vivo they showed decreased directional branch extension toward sites of laser-induced cortical damage (Haynes et al. 2006). Independently from this chemotactic action of ADP, UDP stimulates the uptake of microspheres by rat microglia, and this action was blocked by an antisense oligonucleotide targeting the P2Y6 receptor (Koizumi et al. 2007). These complementary actions of ADP, a find-me signal, and UDP, an eat-me signal, involving a cooperation between P2Y12 and P2Y6, might be beneficial in neurodegenerative conditions such as Alzheimer’s disease, via an increased clearance of amyloid-β deposits.

Summary

Nucleotides are released in the extracellular fluids following cell damage (necrosis or apoptosis), mechanical stimulation, or by exocytosis. They act on G protein–coupled P2Y or ionotropic P2X receptors. There are eight P2Y receptors encoded by distinct genes. They can be divided in two groups according to structural features and coupling to specific G proteins. The P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11 receptors couple mainly to Gq, and the P2Y12, P2Y13, and P2Y14 receptors couple to Gi. They exhibit a selectivity for distinct nucleotides: ATP, ADP, UTP, UDP, and UDP-glucose. The study of knockout mice and other methods of gene silencing have demonstrated their involvement in multiple biological processes: platelet aggregation, epithelial surface lubrication, cardiac development and ischemia, stem cell differentiation, migration of neutrophils, monocytes and microglia, microglial phagocytosis, etc.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Didier Communi
    • 1
  • Bernard Robaye
    • 2
  • Jean-Marie Boeynaems
    • 3
  1. 1.Institute of Interdisciplinary Research, School of MedicineUniversité Libre de BruxellesBrusselsBelgium
  2. 2.Institute of Interdisciplinary Research, School of MedicineUniversité Libre de BruxellesGosselies, BruxellesBelgium
  3. 3.Department of Laboratory Medicine, Erasme Academic HospitalUniversité Libre de BruxellesBrusselsBelgium