Skip to main content
SpringerLink
Log in

An Update on P2Y13 Receptor Signalling and Function

  • Chapter
  • First Online:
Protein Reviews

Part of the book series: Advances in Experimental Medicine and Biology ((PROTRE,volume 1051))

Abstract

The distribution of nucleotide P2Y receptors across different tissues suggests that they fulfil key roles in a number of physiological and pathological conditions. P2Y13 is one of the latest P2Y receptors identified, a novel member of the Gi-coupled P2Y receptor subfamily that responds to ADP, together with P2Y12 and P2Y14. Pharmacological studies drew attention to this new ADP receptor, with a pharmacology that overlaps that of P2Y12 receptors but with unique features and roles. The P2RY12–14 genes all reside on human chromosome 3 at 3q25.1 and their strong sequence homology supports their evolutionary origin through gene duplication. Polymorphisms of P2Y13 receptors have been reported in different human populations, yet their consequences remain unknown. The P2Y13 receptor is versatile in its signalling, extending beyond the canonical signalling of a Gi-coupled receptor. Not only can it couple to different G proteins (Gs/Gq) but the P2Y13 receptor can also trigger several intracellular pathways related to the activation of MAPKs (mitogen-activated protein kinases) and the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3 axis. Moreover, the availability of P2Y13 receptor knockout mice has highlighted the specific functions in which it is involved, mainly in the regulation of cholesterol and glucose metabolism, bone homeostasis and aspects of central nervous system function like pain transmission and neuroprotection. This review summarizes our current understanding of this elusive receptor, not only at the pharmacological and molecular level but also, in terms of its signalling properties and specific functions, helping to clarify the involvement of P2Y13 receptors in pathological situations.

Raquel Pérez-Sen and Rosa Gómez-Villafuertes contributed equally to this work.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

Abbreviations

ADP:

Adenosine 5′-diphosphate.

Ap3A:

P1,P3-Di(adenosine-5′) triphosphate.

Ap4A:

P1,P4-Di(adenosine-5′) triphosphate.

ATP:

Adenosine 5′-triphosphate

cAMP:

Adenosine 3′,5′-cyclic monophosphate.

CT1007900:

(6-[1-(2-Dimethylaminopyrimidin-5-ylmethyl)-piperidin-4-yl]-2-morpholin-4-yl-pyrimidin-4-ol monohydrate).

GPCRs:

G protein–coupled receptors.

GSK3:

Glycogen synthase kinase 3.

HDL:

High density lipoprotein.

2MeSADP:

2-methylthio-adenosine 5′-diphosphate.

MAP kinases:

Mitogen-activated protein kinases.

MRS2211:

2-[(2-Chloro-5-nitrophenyl)azo]-5-hydroxy-6-methyl-3-[(phosphonooxy)methyl]-4-pyridinecarboxaldehyde.

MRS2179:

2′-Deoxy-N6-methyl adenosine 3′,5′-diphosphate.

PLC:

Phospholipase C.

PI3K:

Phosphatidylinositol 3-kinase.

PPADS:

Pyridoxal phosphate-6-azo(benzene-2,4-disulfonic acid).

RCT:

Reverse cholesterol transport

SNP:

Single-nucleotide polymorphism.

References

  • Alexander SP, Davenport AP, Kelly E, Marrion N, Peters JA, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Southan C, Davies JA, Collaborators C (2015) The concise guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. Br J Pharmacol 172(24):5744–5869

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Amisten S, Meidute-Abaraviciene S, Tan C, Olde B, Lundquist I, Salehi A, Erlinge D (2010) ADP mediates inhibition of insulin secretion by activation of P2Y13 receptors in mice. Diabetologia 53(9):1927–1934

    Article  CAS  PubMed  Google Scholar 

  • Ando RD, Mehesz B, Gyires K, Illes P, Sperlagh B (2010) A comparative analysis of the activity of ligands acting at P2X and P2Y receptor subtypes in models of neuropathic, acute and inflammatory pain. Br J Pharmacol 159(5):1106–1117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Biver G, Wang N, Gartland A, Orriss I, Arnett TR, Boeynaems JM, Robaye B (2013) Role of the P2Y13 receptor in the differentiation of bone marrow stromal cells into osteoblasts and adipocytes. Stem Cells 31(12):2747–2758

    Article  CAS  PubMed  Google Scholar 

  • Bjorquist A, Di Buduo CA, Femia EA, Storey RF, Becker RC, Balduini A, Nylander S, Cattaneo M (2016) Studies of the interaction of ticagrelor with the P2Y13 receptor and with P2Y13-dependent pro-platelet formation by human megakaryocytes. Thromb Haemost 116(6):1079–1088

    Article  PubMed  Google Scholar 

  • Blom D, Yamin TT, Champy MF, Selloum M, Bedu E, Carballo-Jane E, Gerckens L, Luell S, Meurer R, Chin J, Mudgett J, Puig O (2010) Altered lipoprotein metabolism in P2Y(13) knockout mice. Biochim Biophys Acta 1801(12):1349–1360

    Article  CAS  PubMed  Google Scholar 

  • Bunyavanich S, Boyce JA, Raby BA, Weiss ST (2012) Gene-by-environment effect of house dust mite on purinergic receptor P2Y12 (P2RY12) and lung function in children with asthma. Clin Exp Allergy 42(2):229–237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carrasquero LM, Delicado EG, Jimenez AI, Perez-Sen R, Miras-Portugal MT (2005) Cerebellar astrocytes co-express several ADP receptors. Presence of functional P2Y(13)-like receptors. Purinergic Signal 1(2):153–159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carrasquero LM, Delicado EG, Bustillo D, Gutierrez-Martin Y, Artalejo AR, Miras-Portugal MT (2009) P2X7 and P2Y13 purinergic receptors mediate intracellular calcium responses to BzATP in rat cerebellar astrocytes. J Neurochem 110(3):879–889

    Article  CAS  PubMed  Google Scholar 

  • Caseley EA, Muench SP, Roger S, Mao HJ, Baldwin SA, Jiang LH (2014) Non-synonymous single nucleotide polymorphisms in the P2X receptor genes: association with diseases, impact on receptor functions and potential use as diagnosis biomarkers. Int J Mol Sci 15(8):13344–13371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cattaneo M, Gachet C (1999) ADP receptors and clinical bleeding disorders. Arterioscler Thromb Vasc Biol 19(10):2281–2285

    Article  CAS  PubMed  Google Scholar 

  • Cavallari U, Trabetti E, Malerba G, Biscuola M, Girelli D, Olivieri O, Martinelli N, Angiolillo DJ, Corrocher R, Pignatti PF (2007) Gene sequence variations of the platelet P2Y12 receptor are associated with coronary artery disease. BMC Med Genet 8:59

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Communi D, Gonzalez NS, Detheux M, Brezillon S, Lannoy V, Parmentier M, Boeynaems JM (2001) Identification of a novel human ADP receptor coupled to G(i). J Biol Chem 276(44):41479–41485

    Article  CAS  PubMed  Google Scholar 

  • Csolle C, Heinrich A, Kittel A, Sperlagh B (2008) P2Y receptor mediated inhibitory modulation of noradrenaline release in response to electrical field stimulation and ischemic conditions in superfused rat hippocampus slices. J Neurochem 106(1):347–360

    Article  CAS  PubMed  Google Scholar 

  • Cuadrado A (2015) Structural and functional characterization of Nrf2 degradation by glycogen synthase kinase 3/beta-TrCP. Free Radic Biol Med 88(Pt B):147–157

    Article  CAS  PubMed  Google Scholar 

  • del Puerto A, Diaz-Hernandez JI, Tapia M, Gomez-Villafuertes R, Benitez MJ, Zhang J, Miras-Portugal MT, Wandosell F, Diaz-Hernandez M, Garrido JJ (2012) Adenylate cyclase 5 coordinates the action of ADP, P2Y1, P2Y13 and ATP-gated P2X7 receptors on axonal elongation. J Cell Sci 125(Pt 1):176–188

    Article  PubMed  CAS  Google Scholar 

  • Diaz-Hernandez JI, Gomez-Villafuertes R, Leon-Otegui M, Hontecillas-Prieto L, Del Puerto A, Trejo JL, Lucas JJ, Garrido JJ, Gualix J, Miras-Portugal MT, Diaz-Hernandez M (2012) In vivo P2X7 inhibition reduces amyloid plaques in Alzheimer’s disease through GSK3beta and secretases. Neurobiol Aging 33(8):1816–1828

    Article  CAS  PubMed  Google Scholar 

  • Dohi T, Morita K, Kitayama T, Motoyama N, Morioka N (2009) Glycine transporter inhibitors as a novel drug discovery strategy for neuropathic pain. Pharmacol Ther 123(1):54–79

    Article  CAS  PubMed  Google Scholar 

  • Dores MR, Trejo J (2012) Ubiquitination of G protein-coupled receptors: functional implications and drug discovery. Mol Pharmacol 82(4):563–570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Espada S, Ortega F, Molina-Jijon E, Rojo AI, Perez-Sen R, Pedraza-Chaverri J, Miras-Portugal MT, Cuadrado A (2010) The purinergic P2Y(13) receptor activates the Nrf2/HO-1 axis and protects against oxidative stress-induced neuronal death. Free Radic Biol Med 49(3):416–426

    Article  CAS  PubMed  Google Scholar 

  • Fabre AC, Malaval C, Ben Addi A, Verdier C, Pons V, Serhan N, Lichtenstein L, Combes G, Huby T, Briand F, Collet X, Nijstad N, Tietge UJ, Robaye B, Perret B, Boeynaems JM, Martinez LO (2010) P2Y13 receptor is critical for reverse cholesterol transport. Hepatology 52(4):1477–1483

    Article  CAS  PubMed  Google Scholar 

  • Ferreira MA, Jansen R, Willemsen G, Penninx B, Bain LM, Vicente CT, Revez JA, Matheson MC, Hui J, Tung JY, Baltic S, Le Souef P, Montgomery GW, Martin NG, Robertson CF, James A, Thompson PJ, Boomsma DI, Hopper JL, Hinds DA, Werder RB, Phipps S, Australian Asthma Genetics Consortium C (2016) Gene-based analysis of regulatory variants identifies 4 putative novel asthma risk genes related to nucleotide synthesis and signaling. J Allergy Clin Immunol 139(4):1148–1157

    Article  PubMed  CAS  Google Scholar 

  • Fumagalli M, Trincavelli L, Lecca D, Martini C, Ciana P, Abbracchio MP (2004) Cloning, pharmacological characterisation and distribution of the rat G-protein-coupled P2Y(13) receptor. Biochem Pharmacol 68(1):113–124

    Article  CAS  PubMed  Google Scholar 

  • Gachet C, Hechler B, Leon C, Vial C, Leray C, Ohlmann P, Cazenave JP (1997) Activation of ADP receptors and platelet function. Thromb Haemost 78(1):271–275

    CAS  PubMed  Google Scholar 

  • Goffinet M, Tardy C, Boubekeur N, Cholez G, Bluteau A, Oniciu DC, Lalwani ND, Dasseux JL, Barbaras R, Baron R (2014) P2Y13 receptor regulates HDL metabolism and atherosclerosis in vivo. PLoS One 9(4):e95807

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gualix J, Fideu MD, Pintor J, Rotllan P, Garcia-Carmona F, Miras-Portugal MT (1997) Characterization of diadenosine polyphosphate transport into chromaffin granules from adrenal medulla. FASEB J 11(12):981–990

    CAS  PubMed  Google Scholar 

  • Gualix J, Gomez-Villafuertes R, Pintor J, Llansola M, Felipo V, Miras-Portugal MT (2014) Presence of diadenosine polyphosphates in microdialysis samples from rat cerebellum in vivo: effect of mild hyperammonemia on their receptors. Purinergic Signal 10(2):349–356

    Article  CAS  PubMed  Google Scholar 

  • Guarracino JF, Cinalli AR, Fernandez V, Roquel LI, Losavio AS (2016) P2Y13 receptors mediate presynaptic inhibition of acetylcholine release induced by adenine nucleotides at the mouse neuromuscular junction. Neuroscience 326:31–44

    Article  CAS  PubMed  Google Scholar 

  • Hechler B, Leon C, Vial C, Vigne P, Frelin C, Cazenave JP, Gachet C (1998) The P2Y1 receptor is necessary for adenosine 5′-diphosphate-induced platelet aggregation. Blood 92(1):152–159

    CAS  PubMed  Google Scholar 

  • Hervas C, Perez-Sen R, Miras-Portugal MT (2003) Coexpression of functional P2X and P2Y nucleotide receptors in single cerebellar granule cells. J Neurosci Res 73(3):384–399

    Article  CAS  PubMed  Google Scholar 

  • Hollopeter G, Jantzen HM, Vincent D, Li G, England L, Ramakrishnan V, Yang RB, Nurden P, Nurden A, Julius D, Conley PB (2001) Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 409(6817):202–207

    Article  CAS  PubMed  Google Scholar 

  • Inoue K, Tsuda M (2012) P2X4 receptors of microglia in neuropathic pain. CNS Neurol Disord Drug Targets 11(6):699–704

    Article  CAS  PubMed  Google Scholar 

  • Jacobson KA, Gao ZG, Paoletta S, Kiselev E, Chakraborty S, Jayasekara PS, Balasubramanian R, Tosh DK (2015) John Daly lecture: structure-guided drug design for adenosine and P2Y receptors. Comput Struct Biotechnol J 13:286–298

    Article  CAS  PubMed  Google Scholar 

  • Jacquet S, Malaval C, Martinez LO, Sak K, Rolland C, Perez C, Nauze M, Champagne E, Terce F, Gachet C, Perret B, Collet X, Boeynaems JM, Barbaras R (2005) The nucleotide receptor P2Y13 is a key regulator of hepatic high-density lipoprotein (HDL) endocytosis. Cell Mol Life Sci 62(21):2508–2515

    Article  CAS  PubMed  Google Scholar 

  • Jimenez AI, Castro E, Mirabet M, Franco R, Delicado EG, Miras-Portugal MT (1999) Potentiation of ATP calcium responses by A2B receptor stimulation and other signals coupled to Gs proteins in type-1 cerebellar astrocytes. Glia 26(2):119–128

    Article  CAS  PubMed  Google Scholar 

  • Jimenez AI, Castro E, Communi D, Boeynaems JM, Delicado EG, Miras-Portugal MT (2000) Coexpression of several types of metabotropic nucleotide receptors in single cerebellar astrocytes. J Neurochem 75(5):2071–2079

    Article  CAS  PubMed  Google Scholar 

  • Jimenez E, Zafra F, Perez-Sen R, Delicado EG, Miras-Portugal MT, Aragon C, Lopez-Corcuera B (2011) P2Y purinergic regulation of the glycine neurotransmitter transporters. J Biol Chem 286(12):10712–10724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Keov P, Sexton PM, Christopoulos A (2011) Allosteric modulation of G protein-coupled receptors: a pharmacological perspective. Neuropharmacology 60(1):24–35

    Article  CAS  PubMed  Google Scholar 

  • Kim YC, Lee JS, Sak K, Marteau F, Mamedova L, Boeynaems JM, Jacobson KA (2005) Synthesis of pyridoxal phosphate derivatives with antagonist activity at the P2Y13 receptor. Biochem Pharmacol 70(2):266–274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim KA, Song WG, Lee HM, Joo HJ, Park JY (2013) Effect of P2Y1 and P2Y12 genetic polymorphisms on the ADP-induced platelet aggregation in a Korean population. Thromb Res 132(2):221–226

    Article  CAS  PubMed  Google Scholar 

  • Kiselev E, Barrett MO, Katritch V, Paoletta S, Weitzer CD, Brown KA, Hammes E, Yin AL, Zhao Q, Stevens RC, Harden TK, Jacobson KA (2014) Exploring a 2-naphthoic acid template for the structure-based design of P2Y14 receptor antagonist molecular probes. ACS Chem Biol 9(12):2833–2842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kobayashi K, Yamanaka H, Fukuoka T, Dai Y, Obata K, Noguchi K (2008) P2Y12 receptor upregulation in activated microglia is a gateway of p38 signaling and neuropathic pain. J Neurosci 28(11):2892–2902

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi K, Yamanaka H, Yanamoto F, Okubo M, Noguchi K (2012) Multiple P2Y subtypes in spinal microglia are involved in neuropathic pain after peripheral nerve injury. Glia 60(10):1529–1539

    Article  PubMed  Google Scholar 

  • Kobayashi K, Yamanaka H, Noguchi K (2013) Expression of ATP receptors in the rat dorsal root ganglion and spinal cord. Anat Sci Int 88(1):10–16

    Article  CAS  PubMed  Google Scholar 

  • Koch H, von Kugelgen I, Starke K (1997) P2-receptor-mediated inhibition of noradrenaline release in the rat hippocampus. Naunyn Schmiedeberg’s Arch Pharmacol 355(6):707–715

    Article  CAS  Google Scholar 

  • Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O’Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, Tukiainen T, Birnbaum DP, Kosmicki JA, Duncan LE, Estrada K, Zhao F, Zou J, Pierce-Hoffman E, Berghout J, Cooper DN, Deflaux N, DePristo M, Do R, Flannick J, Fromer M, Gauthier L, Goldstein J, Gupta N, Howrigan D, Kiezun A, Kurki MI, Moonshine AL, Natarajan P, Orozco L, Peloso GM, Poplin R, Rivas MA, Ruano-Rubio V, Rose SA, Ruderfer DM, Shakir K, Stenson PD, Stevens C, Thomas BP, Tiao G, Tusie-Luna MT, Weisburd B, Won HH, Yu D, Altshuler DM, Ardissino D, Boehnke M, Danesh J, Donnelly S, Elosua R, Florez JC, Gabriel SB, Getz G, Glatt SJ, Hultman CM, Kathiresan S, Laakso M, McCarroll S, McCarthy MI, McGovern D, McPherson R, Neale BM, Palotie A, Purcell SM, Saleheen D, Scharf JM, Sklar P, Sullivan PF, Tuomilehto J, Tsuang MT, Watkins HC, Wilson JG, Daly MJ, MacArthur DG, Exome Aggregation C (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536(7616):285–291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leon C, Hechler B, Vial C, Leray C, Cazenave JP, Gachet C (1997) The P2Y1 receptor is an ADP receptor antagonized by ATP and expressed in platelets and megakaryoblastic cells. FEBS Lett 403(1):26–30

    Article  CAS  PubMed  Google Scholar 

  • Lewis C, Neidhart S, Holy C, North RA, Buell G, Surprenant A (1995) Coexpression of P2X2 and P2X3 receptor subunits can account for ATP-gated currents in sensory neurons. Nature 377(6548):432–435

    Article  CAS  PubMed  Google Scholar 

  • Li MP, Tang J, Wen ZP, Zhang YJ, Zhang W, Zhou HH, Zhang ZL, Chen XP (2015) Influence of P2Y12 polymorphisms on platelet activity but not ex-vivo antiplatelet effect of ticagrelor in healthy Chinese male subjects. Blood Coagul Fibrinolysis 26(8):874–881

    Article  CAS  PubMed  Google Scholar 

  • Lichtenstein L, Serhan N, Annema W, Combes G, Robaye B, Boeynaems JM, Perret B, Tietge UJ, Laffargue M, Martinez LO (2013) Lack of P2Y13 in mice fed a high cholesterol diet results in decreased hepatic cholesterol content, biliary lipid secretion and reverse cholesterol transport. Nutr Metab (Lond) 10(1):67

    Article  CAS  Google Scholar 

  • Lichtenstein L, Serhan N, Espinosa-Delgado S, Fabre A, Annema W, Tietge UJ, Robaye B, Boeynaems JM, Laffargue M, Perret B, Martinez LO (2015) Increased atherosclerosis in P2Y13/apolipoprotein E double-knockout mice: contribution of P2Y13 to reverse cholesterol transport. Cardiovasc Res 106(2):314–323

    Article  CAS  PubMed  Google Scholar 

  • Lordkipanidze M, Pharand C, Schampaert E, Palisaitis DA, Diodati JG (2011) Heterogeneity in platelet cyclooxygenase inhibition by aspirin in coronary artery disease. Int J Cardiol 150(1):39–44

    Article  PubMed  Google Scholar 

  • Lustig KD, Shiau AK, Brake AJ, Julius D (1993) Expression cloning of an ATP receptor from mouse neuroblastoma cells. Proc Natl Acad Sci U S A 90(11):5113–5117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Malaval C, Laffargue M, Barbaras R, Rolland C, Peres C, Champagne E, Perret B, Terce F, Collet X, Martinez LO (2009) RhoA/ROCK I signalling downstream of the P2Y13 ADP-receptor controls HDL endocytosis in human hepatocytes. Cell Signal 21(1):120–127

    Article  CAS  PubMed  Google Scholar 

  • Malin SA, Molliver DC (2010) Gi- and Gq-coupled ADP (P2Y) receptors act in opposition to modulate nociceptive signaling and inflammatory pain behavior. Mol Pain 6:21

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Maqbool M, Mobashir M, Hoda N (2016) Pivotal role of glycogen synthase kinase-3: a therapeutic target for Alzheimer’s disease. Eur J Med Chem 107:63–81

    Article  CAS  PubMed  Google Scholar 

  • Marin-Garcia P, Sanchez-Nogueiro J, Diez A, Leon-Otegui M, Linares M, Garcia-Palencia P, Bautista JM, Miras-Portugal MT (2009) Altered nucleotide receptor expression in a murine model of cerebral malaria. J Infect Dis 200(8):1279–1288

    Article  CAS  PubMed  Google Scholar 

  • Marschallinger J, Schaffner I, Klein B, Gelfert R, Rivera FJ, Illes S, Grassner L, Janssen M, Rotheneichner P, Schmuckermair C, Coras R, Boccazzi M, Chishty M, Lagler FB, Renic M, Bauer HC, Singewald N, Blumcke I, Bogdahn U, Couillard-Despres S, Lie DC, Abbracchio MP, Aigner L (2015) Structural and functional rejuvenation of the aged brain by an approved anti-asthmatic drug. Nat Commun 6:8466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marteau F, Le Poul E, Communi D, Communi D, Labouret C, Savi P, Boeynaems JM, Gonzalez NS (2003) Pharmacological characterization of the human P2Y13 receptor. Mol Pharmacol 64(1):104–112

    Article  CAS  PubMed  Google Scholar 

  • Marteau F, Communi D, Boeynaems JM, Suarez Gonzalez N (2004) Involvement of multiple P2Y receptors and signaling pathways in the action of adenine nucleotides diphosphates on human monocyte-derived dendritic cells. J Leukoc Biol 76(4):796–803

    Article  CAS  PubMed  Google Scholar 

  • Martinez LO, Najib S, Perret B, Cabou C, Lichtenstein L (2015) Ecto-F1-ATPase/P2Y pathways in metabolic and vascular functions of high density lipoproteins. Atherosclerosis 238(1):89–100

    Article  CAS  PubMed  Google Scholar 

  • Marucci G, Dal Ben D, Lambertucci C, Santinelli C, Spinaci A, Thomas A, Volpini R, Buccioni M (2016) The G protein-coupled receptor GPR17: overview and update. ChemMedChem 11(23):2567–2574

    Article  CAS  PubMed  Google Scholar 

  • May LT, Leach K, Sexton PM, Christopoulos A (2007) Allosteric modulation of G protein-coupled receptors. Annu Rev Pharmacol Toxicol 47:1–51

    Article  CAS  PubMed  Google Scholar 

  • Melancon BJ, Hopkins CR, Wood MR, Emmitte KA, Niswender CM, Christopoulos A, Conn PJ, Lindsley CW (2012) Allosteric modulation of seven transmembrane spanning receptors: theory, practice, and opportunities for central nervous system drug discovery. J Med Chem 55(4):1445–1464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Milewicz DM, Seidman CE (2000) Genetics of cardiovascular disease. Circulation 102(20 Suppl 4):IV103–IV111

    CAS  PubMed  Google Scholar 

  • Morente V, Perez-Sen R, Ortega F, Huerta-Cepas J, Delicado EG, Miras-Portugal MT (2014) Neuroprotection elicited by P2Y13 receptors against genotoxic stress by inducing DUSP2 expression and MAPK signaling recovery. Biochim Biophys Acta 1843(9):1886–1898

    Article  CAS  PubMed  Google Scholar 

  • Oestreich JH, Steinhubl SR, Ferraris SP, Loftin CD, Akers WS (2014) Effect of genetic variation in P2Y12 on TRAP-stimulated platelet response in healthy subjects. J Thromb Thrombolysis 38(3):372–379

    Article  CAS  PubMed  Google Scholar 

  • Orriss I, Syberg S, Wang N, Robaye B, Gartland A, Jorgensen N, Arnett T, Boeynaems JM (2011) Bone phenotypes of P2 receptor knockout mice. Front Biosci (Schol Ed) 3:1038–1046

    Article  Google Scholar 

  • Ortega F, Perez-Sen R, Miras-Portugal MT (2008) Gi-coupled P2Y-ADP receptor mediates GSK-3 phosphorylation and beta-catenin nuclear translocation in granule neurons. J Neurochem 104(1):62–73

    CAS  PubMed  Google Scholar 

  • Ortega F, Perez-Sen R, Delicado EG, Teresa Miras-Portugal M (2011) ERK1/2 activation is involved in the neuroprotective action of P2Y13 and P2X7 receptors against glutamate excitotoxicity in cerebellar granule neurons. Neuropharmacology 61(8):1210–1221

    Article  CAS  PubMed  Google Scholar 

  • Ou W, He Y, Li A, Liu B, Jin L (2016) Genotype frequencies of CYP2C19, P2Y12 and GPIIIa polymorphisms in coronary heart disease patients of Han ethnicity, and their impact on Clopidogrel responsiveness. Int Heart J 57(5):586–592

    Article  PubMed  Google Scholar 

  • Paoletta S, Sabbadin D, von Kugelgen I, Hinz S, Katritch V, Hoffmann K, Abdelrahman A, Strassburger J, Baqi Y, Zhao Q, Stevens RC, Moro S, Muller CE, Jacobson KA (2015) Modeling ligand recognition at the P2Y12 receptor in light of X-ray structural information. J Comput Aided Mol Des 29(8):737–756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patel K, Barnes A, Camacho J, Paterson C, Boughtflower R, Cousens D, Marshall F (2001) Activity of diadenosine polyphosphates at P2Y receptors stably expressed in 1321N1 cells. Eur J Pharmacol 430(2–3):203–210

    Article  CAS  PubMed  Google Scholar 

  • Perez-Sen R, Queipo MJ, Morente V, Ortega F, Delicado EG, Miras-Portugal MT (2015) Neuroprotection mediated by P2Y13 nucleotide receptors in neurons. Comput Struct Biotechnol J 13:160–168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pons V, Serhan N, Gayral S, Malaval C, Nauze M, Malet N, Laffargue M, Gales C, Martinez LO (2014) Role of the ubiquitin-proteasome system in the regulation of P2Y13 receptor expression: impact on hepatic HDL uptake. Cell Mol Life Sci 71(9):1775–1788

    Article  CAS  PubMed  Google Scholar 

  • Queiroz G, Talaia C, Goncalves J (2003) ATP modulates noradrenaline release by activation of inhibitory P2Y receptors and facilitatory P2X receptors in the rat vas deferens. J Pharmacol Exp Ther 307(2):809–815

    Article  CAS  PubMed  Google Scholar 

  • Rada P, Rojo AI, Evrard-Todeschi N, Innamorato NG, Cotte A, Jaworski T, Tobon-Velasco JC, Devijver H, Garcia-Mayoral MF, Van Leuven F, Hayes JD, Bertho G, Cuadrado A (2012) Structural and functional characterization of Nrf2 degradation by the glycogen synthase kinase 3/beta-TrCP axis. Mol Cell Biol 32(17):3486–3499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rojo AI, Rada P, Egea J, Rosa AO, Lopez MG, Cuadrado A (2008) Functional interference between glycogen synthase kinase-3 beta and the transcription factor Nrf2 in protection against kainate-induced hippocampal cell death. Mol Cell Neurosci 39(1):125–132

    Article  CAS  PubMed  Google Scholar 

  • Savi P, Beauverger P, Labouret C, Delfaud M, Salel V, Kaghad M, Herbert JM (1998) Role of P2Y1 purinoceptor in ADP-induced platelet activation. FEBS Lett 422(3):291–295

    Article  CAS  PubMed  Google Scholar 

  • Selden NR, Carlson JD, Cetas J, Close LN, Heinricher MM (2007) Purinergic actions on neurons that modulate nociception in the rostral ventromedial medulla. Neuroscience 146(4):1808–1816

    Article  CAS  PubMed  Google Scholar 

  • Serhan N, Cabou C, Verdier C, Lichtenstein L, Malet N, Perret B, Laffargue M, Martinez LO (2013) Chronic pharmacological activation of P2Y13 receptor in mice decreases HDL-cholesterol level by increasing hepatic HDL uptake and bile acid secretion. Biochim Biophys Acta 1831(4):719–725

    Article  CAS  PubMed  Google Scholar 

  • Shaver SR, Rideout JL, Pendergast W, Douglass JG, Brown EG, Boyer JL, Patel RI, Redick CC, Jones AC, Picher M, Yerxa BR (2005) Structure-activity relationships of dinucleotides: potent and selective agonists of P2Y receptors. Purinergic Signal 1(2):183–191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siasos G, Kioufis S, Oikonomou E, Zaromitidou M, Maniatis K, Vavuranakis M, Kokkou E, Tousoulis D (2016) Impact of C34T P2Y12 ADP receptor polymorphism and smoking status on cardiovascular outcome in coronary artery disease patients receiving clopidogrel. Int J Cardiol 210:161–163

    Article  PubMed  Google Scholar 

  • Tan C, Salehi A, Svensson S, Olde B, Erlinge D (2010) ADP receptor P2Y(13) induce apoptosis in pancreatic beta-cells. Cell Mol Life Sci 67(3):445–453

    Article  CAS  PubMed  Google Scholar 

  • Tan C, Voss U, Svensson S, Erlinge D, Olde B (2013) High glucose and free fatty acids induce beta cell apoptosis via autocrine effects of ADP acting on the P2Y(13) receptor. Purinergic Signal 9(1):67–79

    Article  CAS  PubMed  Google Scholar 

  • Tatsumi E, Yamanaka H, Kobayashi K, Yagi H, Sakagami M, Noguchi K (2015) RhoA/ROCK pathway mediates p38 MAPK activation and morphological changes downstream of P2Y12/13 receptors in spinal microglia in neuropathic pain. Glia 63(2):216–228

    Article  PubMed  Google Scholar 

  • Timur AA, Murugesan G, Zhang L, Aung PP, Barnard J, Wang QK, Gaussem P, Silverstein RL, Bhatt DL, Kottke-Marchant K (2012) P2RY1 and P2RY12 polymorphisms and on-aspirin platelet reactivity in patients with coronary artery disease. Int J Lab Hematol 34(5):473–483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tozaki-Saitoh H, Tsuda M, Miyata H, Ueda K, Kohsaka S, Inoue K (2008) P2Y12 receptors in spinal microglia are required for neuropathic pain after peripheral nerve injury. J Neurosci 28(19):4949–4956

    Article  CAS  PubMed  Google Scholar 

  • Van Kolen K, Slegers H (2004) P2Y12 receptor stimulation inhibits beta-adrenergic receptor-induced differentiation by reversing the cyclic AMP-dependent inhibition of protein kinase B. J Neurochem 89(2):442–453

    Article  PubMed  CAS  Google Scholar 

  • Van Kolen K, Gilany K, Moens L, Esmans EL, Slegers H (2006) P2Y12 receptor signalling towards PKB proceeds through IGF-I receptor cross-talk and requires activation of Src, Pyk2 and Rap1. Cell Signal 18(8):1169–1181

    Article  PubMed  CAS  Google Scholar 

  • von Kugelgen I, Hoffmann K (2016) Pharmacology and structure of P2Y receptors. Neuropharmacology 104:50–61

    Article  CAS  Google Scholar 

  • von Kugelgen I, Spath L, Starke K (1994) Evidence for P2-purinoceptor-mediated inhibition of noradrenaline release in rat brain cortex. Br J Pharmacol 113(3):815–822

    Article  Google Scholar 

  • Voss U, Turesson MF, Robaye B, Boeynaems JM, Olde B, Erlinge D, Ekblad E (2014) The enteric nervous system of P2Y13 receptor null mice is resistant against high-fat-diet- and palmitic-acid-induced neuronal loss. Purinergic Signal 10(3):455–464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Z, Nakayama T, Sato N, Yamaguchi M, Izumi Y, Kasamaki Y, Ohta M, Soma M, Aoi N, Ozawa Y, Ma Y, Doba N, Hinohara S (2009a) Purinergic receptor P2Y, G-protein coupled, 2 (P2RY2) gene is associated with cerebral infarction in Japanese subjects. Hypertens Res 32(11):989–996

    Article  CAS  PubMed  Google Scholar 

  • Wang ZX, Nakayama T, Sato N, Izumi Y, Kasamaki Y, Ohta M, Soma M, Aoi N, Matsumoto K, Ozawa Y, Ma YT, Doba N, Hinohara S (2009b) Association of the purinergic receptor P2Y, G-protein coupled, 2 (P2RY2) gene with myocardial infarction in Japanese men. Circ J 73(12):2322–2329

    Article  CAS  PubMed  Google Scholar 

  • Wang Z, Nakayama T, Sato N, Izumi Y, Kasamaki Y, Ohta M, Soma M, Aoi N, Ozawa Y, Ma Y (2010) The purinergic receptor P2Y, G-protein coupled, 2 (P2RY2) gene associated with essential hypertension in Japanese men. J Hum Hypertens 24(5):327–335

    Article  PubMed  CAS  Google Scholar 

  • Wang N, Robaye B, Agrawal A, Skerry TM, Boeynaems JM, Gartland A (2012) Reduced bone turnover in mice lacking the P2Y13 receptor of ADP. Mol Endocrinol 26(1):142–152

    Article  CAS  PubMed  Google Scholar 

  • Wang N, Rumney RM, Yang L, Robaye B, Boeynaems JM, Skerry TM, Gartland A (2013) The P2Y13 receptor regulates extracellular ATP metabolism and the osteogenic response to mechanical loading. J Bone Miner Res 28(6):1446–1456

    Article  CAS  PubMed  Google Scholar 

  • Wang N, Robaye B, Gossiel F, Boeynaems JM, Gartland A (2014) The P2Y13 receptor regulates phosphate metabolism and FGF-23 secretion with effects on skeletal development. FASEB J 28(5):2249–2259

    Article  CAS  PubMed  Google Scholar 

  • Webb TE, Simon J, Krishek BJ, Bateson AN, Smart TG, King BF, Burnstock G, Barnard EA (1993) Cloning and functional expression of a brain G-protein-coupled ATP receptor. FEBS Lett 324(2):219–225

    Article  CAS  PubMed  Google Scholar 

  • Wesselius A, Bours MJ, Henriksen Z, Syberg S, Petersen S, Schwarz P, Jorgensen NR, van Helden S, Dagnelie PC (2013) Association of P2Y(2) receptor SNPs with bone mineral density and osteoporosis risk in a cohort of Dutch fracture patients. Purinergic Signal 9(1):41–49

    Article  CAS  PubMed  Google Scholar 

  • Wirkner K, Schweigel J, Gerevich Z, Franke H, Allgaier C, Barsoumian EL, Draheim H, Illes P (2004) Adenine nucleotides inhibit recombinant N-type calcium channels via G protein-coupled mechanisms in HEK 293 cells; involvement of the P2Y13 receptor-type. Br J Pharmacol 141(1):141–151

    Article  CAS  PubMed  Google Scholar 

  • Yano S, Tsukimoto M, Harada H, Kojima S (2012) Involvement of P2Y13 receptor in suppression of neuronal differentiation. Neurosci Lett 518(1):5–9

    Article  CAS  PubMed  Google Scholar 

  • Zee RY, Michaud SE, Diehl KA, Chasman DI, Emmerich J, Gaussem P, Aiach M, Ridker PM (2008) Purinergic receptor P2Y, G-protein coupled, 12 gene variants and risk of incident ischemic stroke, myocardial infarction, and venous thromboembolism. Atherosclerosis 197(2):694–699

    Article  CAS  PubMed  Google Scholar 

  • Zhang FL, Luo L, Gustafson E, Lachowicz J, Smith M, Qiao XD, Liu YH, Chen GD, Pramanik B, Laz TM, Palmer K, Bayne M, Monsma FJ (2001) ADP is the cognate ligand for the orphan G protein-coupled receptor SP1999. J Biol Chem 276(11):8608–8615

    Article  CAS  PubMed  Google Scholar 

  • Zhang FL, Luo L, Gustafson E, Palmer K, Qiao X, Fan X, Yang S, Laz TM, Bayne M, Monsma F Jr (2002) P2Y(13): identification and characterization of a novel Galphai-coupled ADP receptor from human and mouse. J Pharmacol Exp Ther 301(2):705–713

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Zhang K, Gao ZG, Paoletta S, Zhang D, Han GW, Li T, Ma L, Zhang W, Muller CE, Yang H, Jiang H, Cherezov V, Katritch V, Jacobson KA, Stevens RC, Wu B, Zhao Q (2014a) Agonist-bound structure of the human P2Y12 receptor. Nature 509(7498):119–122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang K, Zhang J, Gao ZG, Zhang D, Zhu L, Han GW, Moss SM, Paoletta S, Kiselev E, Lu W, Fenalti G, Zhang W, Muller CE, Yang H, Jiang H, Cherezov V, Katritch V, Jacobson KA, Stevens RC, Wu B, Zhao Q (2014b) Structure of the human P2Y12 receptor in complex with an antithrombotic drug. Nature 509(7498):115–118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng X, Liang Y, Kang A, Ma SJ, Xing L, Zhou YY, Dai C, Xie H, Xie L, Wang GJ, Hao HP (2014) Peripheral immunomodulation with ginsenoside Rg1 ameliorates neuroinflammation-induced behavioral deficits in rats. Neuroscience 256:210–222

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We are grateful to Dr. Mark Sefton for the english copy-editing of the manuscript. The work in the authors’ laboratory is funded by the Spanish Ministerio de Economia y Competitividad (MINECO, BFU 2014-53654-P) and Red de excelencia Consolider-Ingenio Spanish Ion Channel Initiative” (BFU2015-70067REDC); by the Comunidad de Madrid (BRADE-CM S2013/ICE-2958), UCM-Santander (PR26/16-18B-3) and by the Fundación Ramón Areces Grant (PR2018/16-02). F. Ortega is a recipient of a Ramón y Cajal contract (RYC-2013-13290).

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Ethical Approvals

This article does not contain any studies with human participants or animals performed by any of the authors.

Author information

Author notes

    Authors and Affiliations

    1. Departamento de Bioquímica y Biología Molecular IV, Facultad de Veterinaria, Instituto Universitario de Investigación en Neuroquímica, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Universidad Complutense Madrid, 28040, Madrid, Spain

      Raquel Pérez-Sen, Rosa Gómez-Villafuertes, Felipe Ortega, Javier Gualix, Esmerilda G. Delicado & María Teresa Miras-Portugal

    Authors
    1. Raquel Pérez-Sen
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Rosa Gómez-Villafuertes
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Felipe Ortega
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Javier Gualix
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Esmerilda G. Delicado
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. María Teresa Miras-Portugal
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Esmerilda G. Delicado or María Teresa Miras-Portugal .

    Editor information

    Editors and Affiliations

    1. Biochem and Mol Biol, Baylor College of Medicine, Houston, Texas, USA

      M. Zouhair Atassi

    Rights and permissions

    Reprints and permissions

    Copyright information

    © 2017 Springer Nature Singapore Pte Ltd.

    About this chapter

    Cite this chapter

    Pérez-Sen, R., Gómez-Villafuertes, R., Ortega, F., Gualix, J., Delicado, E.G., Miras-Portugal, M.T. (2017). An Update on P2Y13 Receptor Signalling and Function. In: Atassi, M. (eds) Protein Reviews. Advances in Experimental Medicine and Biology(), vol 1051. Springer, Singapore. https://doi.org/10.1007/5584_2017_91

    Download citation

    Publish with us

    Policies and ethics

    Search

    Navigation