Skip to main content

Advertisement

SpringerLink
Log in

Therapeutic potential for P2Y2 receptor antagonism

  • Review Article
  • Published:
Purinergic Signalling Aims and scope Submit manuscript

Abstract

G protein-coupled receptors are the target of more than 30% of all FDA-approved drug therapies. Though the purinergic P2 receptors have been an attractive target for therapeutic intervention with successes such as the P2Y12 receptor antagonist, clopidogrel, P2Y2 receptor (P2Y2R) antagonism remains relatively unexplored as a therapeutic strategy. Due to a lack of selective antagonists to modify P2Y2R activity, studies using primarily genetic manipulation have revealed roles for P2Y2R in a multitude of diseases. These include inflammatory and autoimmune diseases, fibrotic diseases, renal diseases, cancer, and pathogenic infections. With the advent of AR-C118925, a selective and potent P2Y2R antagonist that became commercially available only a few years ago, new opportunities exist to gain a more robust understanding of P2Y2R function and assess therapeutic effects of P2Y2R antagonism. This review discusses the characteristics of P2Y2R that make it unique among P2 receptors, namely its involvement in five distinct signaling pathways including canonical Gαq protein signaling. We also discuss the effects of other P2Y2R antagonists and the pivotal development of AR-C118925. The remainder of this review concerns the mounting evidence implicating P2Y2Rs in disease pathogenesis, focusing on those studies that have evaluated AR-C118925 in pre-clinical disease models.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Scheme 1

Similar content being viewed by others

Data availability

Not applicable.

References

  1. Di Virgilio F, Sarti AC, Falzoni S, De Marchi E, Adinolfi E (2018) Extracellular ATP and P2 purinergic signalling in the tumour microenvironment. Nat Rev Cancer 18(10):601–618

    Article  PubMed  Google Scholar 

  2. Zuccarini M, Giuliani P, Ronci M, Caciagli F, Caruso V, Ciccarelli R et al (2022) Purinergic signaling in oral tissues. Int J Mol Sci 23(14):7790

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Woods LT, Forti KM, Shanbhag VC, Camden JM, Weisman GA (2021) P2Y receptors for extracellular nucleotides: contributions to cancer progression and therapeutic implications. Biochem Pharmacol 187:114406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Volonte C, D’Ambrosi N (2009) Membrane compartments and purinergic signalling: the purinome, a complex interplay among ligands, degrading enzymes, receptors and transporters. FEBS J 276(2):318–329

    Article  CAS  PubMed  Google Scholar 

  5. Murray JM, Bussiere DE (2009) Targeting the purinome. Methods Mol Biol 575:47–92

    Article  CAS  PubMed  Google Scholar 

  6. Huang Z, Xie N, Illes P, Di Virgilio F, Ulrich H, Semyanov A et al (2021) From purines to purinergic signalling: molecular functions and human diseases. Signal Transduct Target Ther 6(1):162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Khalafalla MG, Woods LT, Jasmer KJ, Forti KM, Camden JM, Jensen JL et al (2020) P2 Receptors as therapeutic targets in the salivary gland: from physiology to dysfunction. Front Pharmacol 11:222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kishore SP, Blank E, Heller DJ, Patel A, Peters A, Price M et al (2018) Modernizing the World Health Organization list of Essential Medicines for preventing and controlling cardiovascular diseases. J Am Coll Cardiol 71(5):564–574

    Article  PubMed  Google Scholar 

  9. Schupke S, Neumann FJ, Menichelli M, Mayer K, Bernlochner I, Wohrle J et al (2019) Ticagrelor or Prasugrel in patients with acute coronary syndromes. N Engl J Med 381(16):1524–1534

    Article  CAS  PubMed  Google Scholar 

  10. Smith JA, Kitt MM, Morice AH, Birring SS, McGarvey LP, Sher MR et al (2020) Gefapixant, a P2X3 receptor antagonist, for the treatment of refractory or unexplained chronic cough: a randomised, double-blind, controlled, parallel-group, phase 2b trial. Lancet Respir Med 8(8):775–785

    Article  CAS  PubMed  Google Scholar 

  11. McGarvey LP, Birring SS, Morice AH, Dicpinigaitis PV, Pavord ID, Schelfhout J et al (2022) Efficacy and safety of gefapixant, a P2X3 receptor antagonist, in refractory chronic cough and unexplained chronic cough (COUGH-1 and COUGH-2): results from two double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials. Lancet 399(10328):909–923

    Article  PubMed  Google Scholar 

  12. Markham A (2022) Gefapixant: first approval. Drugs 82(6):691–695

    Article  PubMed  Google Scholar 

  13. Smith JLM, Birring SS, Morice AH, Sher MR, Dicpinigaitis P, Blaiss M, Lanouette S, Harvey L, Yang R, Shaw J, Garin M, Bonuccelli CM (2022) Safety and efficacy of BLU-5937 in the treatment of refractory chronic cough from the phase 2b soothe trial. American Thoracic Society International Conference, San Francisco

  14. Garceau D, Chauret N (2019) BLU-5937: a selective P2X3 antagonist with potent anti-tussive effect and no taste alteration. Pulm Pharmacol Ther 56:56–62

    Article  CAS  PubMed  Google Scholar 

  15. Stock TC, Bloom BJ, Wei N, Ishaq S, Park W, Wang X et al (2012) Efficacy and safety of CE-224,535, an antagonist of P2X7 receptor, in treatment of patients with rheumatoid arthritis inadequately controlled by methotrexate. J Rheumatol 39(4):720–727

    Article  CAS  PubMed  Google Scholar 

  16. Drill M, Jones NC, Hunn M, O’Brien TJ, Monif M (2021) Antagonism of the ATP-gated P2X7 receptor: a potential therapeutic strategy for cancer. Purinergic Signal 17(2):215–227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Keystone EC, Wang MM, Layton M, Hollis S, McInnes IB, Team DCS (2012) Clinical evaluation of the efficacy of the P2X7 purinergic receptor antagonist AZD9056 on the signs and symptoms of rheumatoid arthritis in patients with active disease despite treatment with methotrexate or sulphasalazine. Ann Rheum Dis 71(10):1630–1635

    Article  CAS  PubMed  Google Scholar 

  18. Eser A, Colombel JF, Rutgeerts P, Vermeire S, Vogelsang H, Braddock M et al (2015) Safety and efficacy of an oral inhibitor of the purinergic receptor P2X7 in adult patients with moderately to severely active Crohn’s disease: a randomized placebo-controlled, double-blind. Phase IIa study Inflamm Bowel Dis 21(10):2247–2253

    PubMed  Google Scholar 

  19. Jacob F, Perez Novo C, Bachert C, Van Crombruggen K (2013) Purinergic signaling in inflammatory cells: P2 receptor expression, functional effects, and modulation of inflammatory responses. Purinergic Signal 9(3):285–306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Idzko M, Ferrari D, Eltzschig HK (2014) Nucleotide signalling during inflammation. Nature 509(7500):310–317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Elliott MR, Chekeni FB, Trampont PC, Lazarowski ER, Kadl A, Walk SF et al (2009) Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 461(7261):282–286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ferrari D, la Sala A, Panther E, Norgauer J, Di Virgilio F, Idzko M (2006) Activation of human eosinophils via P2 receptors: novel findings and future perspectives. J Leukoc Biol 79(1):7–15

    Article  CAS  PubMed  Google Scholar 

  23. Chen Y, Corriden R, Inoue Y, Yip L, Hashiguchi N, Zinkernagel A et al (2006) ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors. Science 314(5806):1792–1795

    Article  CAS  PubMed  Google Scholar 

  24. Parr CE, Sullivan DM, Paradiso AM, Lazarowski ER, Burch LH, Olsen JC et al (1994) Cloning and expression of a human P2U nucleotide receptor, a target for cystic fibrosis pharmacotherapy. Proc Natl Acad Sci U S A 91(8):3275–3279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Erb L, Liao Z, Seye CI, Weisman GA (2006) P2 receptors: intracellular signaling. Pflugers Arch 452(5):552–562

    Article  CAS  PubMed  Google Scholar 

  26. Erb L, Liu J, Ockerhausen J, Kong Q, Garrad RC, Griffin K et al (2001) An RGD sequence in the P2Y2 receptor interacts with αVβ3 integrins and is required for G(o)-mediated signal transduction. J Cell Biol 153(3):491–501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Liao Z, Seye CI, Weisman GA, Erb L (2007) The P2Y2 nucleotide receptor requires interaction with αv integrins to access and activate G12. J Cell Sci 120(Pt 9):1654–1662

    Article  CAS  PubMed  Google Scholar 

  28. Bagchi S, Liao Z, Gonzalez FA, Chorna NE, Seye CI, Weisman GA et al (2005) The P2Y2 nucleotide receptor interacts with αv integrins to activate Go and induce cell migration. J Biol Chem 280(47):39050–39057

    Article  CAS  PubMed  Google Scholar 

  29. El-Sayed FG, Camden JM, Woods LT, Khalafalla MG, Petris MJ, Erb L et al (2014) P2Y2 nucleotide receptor activation enhances the aggregation and self-organization of dispersed salivary epithelial cells. Am J Physiol Cell Physiol 307(1):C83-96

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Siehler S (2009) Regulation of RhoGEF proteins by G12/13-coupled receptors. Br J Pharmacol 158(1):41–49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Welch HC, Coadwell WJ, Ellson CD, Ferguson GJ, Andrews SR, Erdjument-Bromage H et al (2002) P-Rex1, a PtdIns(3,4,5)P3- and Gβγ-regulated guanine-nucleotide exchange factor for Rac. Cell 108(6):809–821

    Article  CAS  PubMed  Google Scholar 

  32. Brown E (2001) Integrin-associated protein (CD47): an unusual activator of G protein signaling. J Clin Invest 107(12):1499–1500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Liu J, Liao Z, Camden J, Griffin KD, Garrad RC, Santiago-Perez LI et al (2004) Src homology 3 binding sites in the P2Y2 nucleotide receptor interact with Src and regulate activities of Src, proline-rich tyrosine kinase 2, and growth factor receptors. J Biol Chem 279(9):8212–8218

    Article  CAS  PubMed  Google Scholar 

  34. Seye CI, Yu N, Gonzalez FA, Erb L, Weisman GA (2004) The P2Y2 nucleotide receptor mediates vascular cell adhesion molecule-1 expression through interaction with VEGF receptor-2 (KDR/Flk-1). J Biol Chem 279(34):35679–35686

    Article  CAS  PubMed  Google Scholar 

  35. Soltoff SP (1998) Related adhesion focal tyrosine kinase and the epidermal growth factor receptor mediate the stimulation of mitogen-activated protein kinase by the G-protein-coupled P2Y2 receptor. Phorbol ester or [Ca2+]i elevation can substitute for receptor activation. J Biol Chem. 273(36):23110–7

    Article  CAS  PubMed  Google Scholar 

  36. Yu N, Erb L, Shivaji R, Weisman GA, Seye CI (2008) Binding of the P2Y2 nucleotide receptor to filamin A regulates migration of vascular smooth muscle cells. Circ Res 102(5):581–588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Woods LT, Jasmer KJ, Munoz Forti K, Shanbhag VC, Camden JM, Erb L et al (2020) P2Y2 receptors mediate nucleotide-induced EGFR phosphorylation and stimulate proliferation and tumorigenesis of head and neck squamous cell carcinoma cell lines. Oral Oncol 109:104808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ratchford AM, Baker OJ, Camden JM, Rikka S, Petris MJ, Seye CI et al (2010) P2Y2 nucleotide receptors mediate metalloprotease-dependent phosphorylation of epidermal growth factor receptor and ErbB3 in human salivary gland cells. J Biol Chem 285(10):7545–7555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Camden JM, Schrader AM, Camden RE, Gonzalez FA, Erb L, Seye CI et al (2005) P2Y2 nucleotide receptors enhance α-secretase-dependent amyloid precursor protein processing. J Biol Chem 280(19):18696–18702

    Article  CAS  PubMed  Google Scholar 

  40. Sahin U, Weskamp G, Kelly K, Zhou HM, Higashiyama S, Peschon J et al (2004) Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands. J Cell Biol 164(5):769–779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zbodakova O, Chalupsky K, Sarnova L, Kasparek P, Jirouskova M, Gregor M et al (2021) ADAM10 and ADAM17 regulate EGFR, c-Met and TNF RI signalling in liver regeneration and fibrosis. Sci Rep 11(1):11414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Muller T, Robaye B, Vieira RP, Ferrari D, Grimm M, Jakob T et al (2010) The purinergic receptor P2Y2 receptor mediates chemotaxis of dendritic cells and eosinophils in allergic lung inflammation. Allergy 65(12):1545–1553

    Article  CAS  PubMed  Google Scholar 

  43. Jasmer KJ, Woods LT, Forti KM, Martin AL, Camden JM, Colonna M et al (2021) P2Y2 receptor antagonism resolves sialadenitis and improves salivary flow in a Sjogren’s syndrome mouse model. Arch Oral Biol 124:105067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ferrari D, Idzko M, Dichmann S, Purlis D, Virchow C, Norgauer J et al (2000) P2 purinergic receptors of human eosinophils: characterization and coupling to oxygen radical production. FEBS Lett 486(3):217–224

    Article  CAS  PubMed  Google Scholar 

  45. Jin J, Dasari VR, Sistare FD, Kunapuli SP (1998) Distribution of P2Y receptor subtypes on haematopoietic cells. Br J Pharmacol 123(5):789–794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wang L, Jacobsen SE, Bengtsson A, Erlinge D (2004) P2 receptor mRNA expression profiles in human lymphocytes, monocytes and CD34+ stem and progenitor cells. BMC Immunol 5:16

    Article  PubMed  PubMed Central  Google Scholar 

  47. Gorini S, Callegari G, Romagnoli G, Mammi C, Mavilio D, Rosano G et al (2010) ATP secreted by endothelial cells blocks CX(3)CL 1-elicited natural killer cell chemotaxis and cytotoxicity via P2Y(1)(1) receptor activation. Blood 116(22):4492–4500

    Article  CAS  PubMed  Google Scholar 

  48. Woods LT, Camden JM, Khalafalla MG, Petris MJ, Erb L, Ambrus JL Jr et al (2018) P2Y2 R deletion ameliorates sialadenitis in IL-14α-transgenic mice. Oral Dis 24(5):761–771

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Harjunpaa H, Llort Asens M, Guenther C, Fagerholm SC (2019) Cell adhesion molecules and their roles and regulation in the immune and tumor microenvironment. Front Immunol 10:1078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Baker OJ, Camden JM, Rome DE, Seye CI, Weisman GA (2008) P2Y2 nucleotide receptor activation up-regulates vascular cell adhesion molecule-1 [corrected] expression and enhances lymphocyte adherence to a human submandibular gland cell line. Mol Immunol 45(1):65–75

    Article  CAS  PubMed  Google Scholar 

  51. Keating GM (2015) Diquafosol ophthalmic solution 3%: a review of its use in dry eye. Drugs 75(8):911–922

    Article  CAS  PubMed  Google Scholar 

  52. Moss RB (2013) Pitfalls of drug development: lessons learned from trials of denufosol in cystic fibrosis. J Pediatr 162(4):676–680

    Article  PubMed  Google Scholar 

  53. Accurso FJ, Moss RB, Wilmott RW, Anbar RD, Schaberg AE, Durham TA et al (2011) Denufosol tetrasodium in patients with cystic fibrosis and normal to mildly impaired lung function. Am J Respir Crit Care Med 183(5):627–634

    Article  CAS  PubMed  Google Scholar 

  54. Rafehi M, Muller CE (2018) Tools and drugs for uracil nucleotide-activated P2Y receptors. Pharmacol Ther 190:24–80

    Article  CAS  PubMed  Google Scholar 

  55. Xu P, Feng X, Luan H, Wang J, Ge R, Li Z et al (2018) Current knowledge on the nucleotide agonists for the P2Y2 receptor. Bioorg Med Chem 26(2):366–375

    Article  CAS  PubMed  Google Scholar 

  56. von Kugelgen I (2019) Pharmacology of P2Y receptors. Brain Res Bull 151:12–24

    Article  Google Scholar 

  57. Communi D, Robaye B, Boeynaems JM (1999) Pharmacological characterization of the human P2Y11 receptor. Br J Pharmacol 128(6):1199–1206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Pillaiyar T, Funke M, Al-Hroub H, Weyler S, Ivanova S, Schlegel J et al (2020) Design, synthesis and biological evaluation of suramin-derived dual antagonists of the proinflammatory G protein-coupled receptors P2Y2 and GPR17. Eur J Med Chem 186:111789

    Article  CAS  PubMed  Google Scholar 

  59. Jacobson KA, Muller CE (2016) Medicinal chemistry of adenosine, P2Y and P2X receptors. Neuropharmacology 104:31–49

    Article  CAS  PubMed  Google Scholar 

  60. Rafehi M, Malik EM, Neumann A, Abdelrahman A, Hanck T, Namasivayam V et al (2017) Development of potent and selective antagonists for the UTP-activated P2Y4 receptor. J Med Chem 60(7):3020–3038

    Article  CAS  PubMed  Google Scholar 

  61. Kaulich MFS, Mayer R, Müller I, Müller CE (2003) Flavonoids—novel lead compounds for the development of P2Y2 receptor antagonists. Drug Dev Res 59:72–81

    Article  CAS  Google Scholar 

  62. Kindon N, Davis A, Dougall I, Dixon J, Johnson T, Walters I et al (2017) From UTP to AR-C118925, the discovery of a potent non nucleotide antagonist of the P2Y2 receptor. Bioorg Med Chem Lett 27(21):4849–4853

    Article  CAS  PubMed  Google Scholar 

  63. Kindon N, Meghani P, Thom SNC (1999) Astrazeneca AB. Novel Compounds. WO1999002501

  64. Mohamady S, Jakeman DL (2005) An improved method for the synthesis of nucleoside triphosphate analogues. J Org Chem 70(25):10588–10591

    Article  CAS  PubMed  Google Scholar 

  65. El-Tayeb A, Qi A, Muller CE (2006) Synthesis and structure-activity relationships of uracil nucleotide derivatives and analogues as agonists at human P2Y2, P2Y4, and P2Y6 receptors. J Med Chem 49(24):7076–7087

    Article  CAS  PubMed  Google Scholar 

  66. El-Tayeb A, Qi A, Nicholas RA, Muller CE (2011) Structural modifications of UMP, UDP, and UTP leading to subtype-selective agonists for P2Y2, P2Y4, and P2Y6 receptors. J Med Chem 54(8):2878–2890

    Article  CAS  PubMed  Google Scholar 

  67. Leeson PD, Springthorpe B (2007) The influence of drug-like concepts on decision-making in medicinal chemistry. Nat Rev Drug Discov 6(11):881–890

    Article  CAS  PubMed  Google Scholar 

  68. Meghani P (2002) The design of P2Y2 antagonists for the treatment of inflammatory diseases. 224th ACS National Meeting. American Chemical Society, Boston

    Google Scholar 

  69. Kemp PA, Sugar RA, Jackson AD (2004) Nucleotide-mediated mucin secretion from differentiated human bronchial epithelial cells. Am J Respir Cell Mol Biol 31(4):446–455

    Article  CAS  PubMed  Google Scholar 

  70. Rafehi M, Burbiel JC, Attah IY, Abdelrahman A, Muller CE (2017) Synthesis, characterization, and in vitro evaluation of the selective P2Y2 receptor antagonist AR-C118925. Purinergic Signal 13(1):89–103

    Article  CAS  PubMed  Google Scholar 

  71. Henriquez M, Fonseca M, Perez-Zoghbi JF (2018) Purinergic receptor stimulation induces calcium oscillations and smooth muscle contraction in small pulmonary veins. J Physiol 596(13):2491–2506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Perera LMB, Sekiguchi A, Uchiyama A, Uehara A, Fujiwara C, Yamazaki S et al (2019) The regulation of skin fibrosis in systemic sclerosis by extracellular ATP via P2Y2 purinergic receptor. J Invest Dermatol 139(4):890–899

    Article  CAS  PubMed  Google Scholar 

  73. Dai X, Tohyama M, Murakami M, Shiraishi K, Liu S, Mori H et al (2020) House dust mite allergens induce interleukin 33 (IL-33) synthesis and release from keratinocytes via ATP-mediated extracellular signaling. Biochim Biophys Acta Mol Basis Dis 1866(5):165719

    Article  CAS  PubMed  Google Scholar 

  74. Hu LP, Zhang XX, Jiang SH, Tao LY, Li Q, Zhu LL et al (2019) Targeting purinergic receptor P2Y2 prevents the growth of pancreatic ductal adenocarcinoma by inhibiting cancer cell glycolysis. Clin Cancer Res 25(4):1318–1330

    Article  CAS  PubMed  Google Scholar 

  75. Tariba Knezevic P, Vukman R, Uhac M, Illes D, Kovacevic Pavicic D, Simonic-Kocijan S (2020) P2Y2 receptors mediate masseter muscle mechanical hypersensitivity in rats. J Pain Res 13:1323–1333

    Article  PubMed  PubMed Central  Google Scholar 

  76. Magni G, Merli D, Verderio C, Abbracchio MP, Ceruti S (2015) P2Y2 receptor antagonists as anti-allodynic agents in acute and sub-chronic trigeminal sensitization: role of satellite glial cells. Glia 63(7):1256–1269

    Article  PubMed  Google Scholar 

  77. Di Virgilio F, Sarti AC, Coutinho-Silva R (2020) Purinergic signaling, DAMPs, and inflammation. Am J Physiol Cell Physiol 318(5):C832–C835

    Article  PubMed  Google Scholar 

  78. Luttikhuizen DT, Harmsen MC, de Leij LF, van Luyn MJ (2004) Expression of P2 receptors at sites of chronic inflammation. Cell Tissue Res 317(3):289–298

    Article  CAS  PubMed  Google Scholar 

  79. Khalafalla MG, Woods LT, Camden JM, Khan AA, Limesand KH, Petris MJ et al (2017) P2X7 receptor antagonism prevents IL-1β release from salivary epithelial cells and reduces inflammation in a mouse model of autoimmune exocrinopathy. J Biol Chem 292(40):16626–16637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Di Virgilio F (2007) Liaisons dangereuses: P2X(7) and the inflammasome. Trends Pharmacol Sci 28(9):465–472

    Article  PubMed  Google Scholar 

  81. Peterson TS, Thebeau CN, Ajit D, Camden JM, Woods LT, Wood WG et al (2013) Up-regulation and activation of the P2Y(2) nucleotide receptor mediate neurite extension in IL-1β-treated mouse primary cortical neurons. J Neurochem 125(6):885–896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kong Q, Peterson TS, Baker O, Stanley E, Camden J, Seye CI et al (2009) Interleukin-1 β enhances nucleotide-induced and α-secretase-dependent amyloid precursor protein processing in rat primary cortical neurons via up-regulation of the P2Y(2) receptor. J Neurochem 109(5):1300–1310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Jin H, Ko YS, Kim HJ (2018) P2Y2R-mediated inflammasome activation is involved in tumor progression in breast cancer cells and in radiotherapy-resistant breast cancer. Int J Oncol 53(5):1953–1966

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Baer AN, Hammitt KM (2021) Sjogren’s disease, not syndrome. Arthritis Rheumatol 73(7):1347–1348

    Article  PubMed  Google Scholar 

  85. Ramos-Casals M, Brito-Zeron P, Bombardieri S, Bootsma H, De Vita S, Dorner T et al (2020) EULAR recommendations for the management of Sjogren’s syndrome with topical and systemic therapies. Ann Rheum Dis 79(1):3–18

    Article  CAS  PubMed  Google Scholar 

  86. Mariette X, Criswell LA (2018) Primary Sjogren’s syndrome. N Engl J Med 378(10):931–939

    Article  PubMed  Google Scholar 

  87. Li L, Jasmer KJ, Camden JM, Woods LT, Martin AL, Yang Y et al (2022) Early dry eye disease onset in a NOD.H-2h4 mouse model of Sjogren’s syndrome. Invest Ophthalmol Vis Sci 63(6):18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Kvarnstrom M, Ottosson V, Nordmark B, Wahren-Herlenius M (2015) Incident cases of primary Sjogren’s syndrome during a 5-year period in Stockholm County: a descriptive study of the patients and their characteristics. Scand J Rheumatol 44(2):135–142

    Article  CAS  PubMed  Google Scholar 

  89. Brandt JE, Priori R, Valesini G, Fairweather D (2015) Sex differences in Sjogren’s syndrome: a comprehensive review of immune mechanisms. Biol Sex Differ 6:19

    Article  PubMed  PubMed Central  Google Scholar 

  90. Malladi AS, Sack KE, Shiboski SC, Shiboski CH, Baer AN, Banushree R et al (2012) Primary Sjogren’s syndrome as a systemic disease: a study of participants enrolled in an international Sjogren’s syndrome registry. Arthritis Care Res (Hoboken) 64(6):911–918

    Article  PubMed  Google Scholar 

  91. van Nimwegen JF, van der Tuuk K, Liefers SC, Verstappen GM, Visser A, Wijnsma RF et al (2020) Vaginal dryness in primary Sjogren’s syndrome: a histopathological case-control study. Rheumatology (Oxford) 59(10):2806–2815

    Article  PubMed  Google Scholar 

  92. Both T, Dalm VA, van Hagen PM, van Daele PL (2017) Reviewing primary Sjogren’s syndrome: beyond the dryness - from pathophysiology to diagnosis and treatment. Int J Med Sci 14(3):191–200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Nocturne G, Mariette X (2015) Sjogren syndrome-associated lymphomas: an update on pathogenesis and management. Br J Haematol 168(3):317–327

    Article  CAS  PubMed  Google Scholar 

  94. Mathews SA, Kurien BT, Scofield RH (2008) Oral manifestations of Sjogren’s syndrome. J Dent Res 87(4):308–318

    Article  CAS  PubMed  Google Scholar 

  95. Mortazavi H, Baharvand M, Movahhedian A, Mohammadi M, Khodadoustan A (2014) Xerostomia due to systemic disease: a review of 20 conditions and mechanisms. Ann Med Health Sci Res 4(4):503–510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Stojan G, Baer AN, Danoff SK (2013) Pulmonary manifestations of Sjogren’s syndrome. Curr Allergy Asthma Rep 13(4):354–360

    Article  PubMed  PubMed Central  Google Scholar 

  97. Parambil JG, Myers JL, Lindell RM, Matteson EL, Ryu JH (2006) Interstitial lung disease in primary Sjogren syndrome. Chest 130(5):1489–1495

    Article  PubMed  Google Scholar 

  98. Ramos-Casals M, Tzioufas AG, Stone JH, Siso A, Bosch X (2010) Treatment of primary Sjogren syndrome: a systematic review. JAMA 304(4):452–460

    Article  CAS  PubMed  Google Scholar 

  99. McCoy SS, Woodham M, Bunya VY, Saldanha IJ, Akpek EK, Makara MA et al (2022) A comprehensive overview of living with Sjogren’s: results of a National Sjogren’s Foundation survey. Clin Rheumatol 41(7):2071–2078

    Article  PubMed  Google Scholar 

  100. Martel C, Gondran G, Launay D, Lalloue F, Palat S, Lambert M et al (2011) Active immunological profile is associated with systemic Sjogren’s syndrome. J Clin Immunol 31(5):840–847

    Article  CAS  PubMed  Google Scholar 

  101. Liang Y, Yang Z, Qin B, Zhong R (2014) Primary Sjogren’s syndrome and malignancy risk: a systematic review and meta-analysis. Ann Rheum Dis 73(6):1151–1156

    Article  PubMed  Google Scholar 

  102. Hansen A, Odendahl M, Reiter K, Jacobi AM, Feist E, Scholze J et al (2002) Diminished peripheral blood memory B cells and accumulation of memory B cells in the salivary glands of patients with Sjogren’s syndrome. Arthritis Rheum 46(8):2160–2171

    Article  CAS  PubMed  Google Scholar 

  103. Du W, Han M, Zhu X, Xiao F, Huang E, Che N et al (2021) The multiple roles of B Cells in the pathogenesis of Sjogren’s syndrome. Front Immunol 12:684999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Gao Y, Chen Y, Zhang Z, Yu X, Zheng J (2020) Recent advances in mouse models of Sjogren’s syndrome. Front Immunol 11:1158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Shen L, Zhang C, Wang T, Brooks S, Ford RJ, Lin-Lee YC et al (2006) Development of autoimmunity in IL-14α-transgenic mice. J Immunol 177(8):5676–5686

    Article  CAS  PubMed  Google Scholar 

  106. Kayes TD, Weisman GA, Camden JM, Woods LT, Bredehoeft C, Downey EF et al (2016) New murine model of early onset autoimmune thyroid disease/hypothyroidism and autoimmune exocrinopathy of the salivary gland. J Immunol 197(6):2119–2130

    Article  CAS  PubMed  Google Scholar 

  107. Schrader AM, Camden JM, Weisman GA (2005) P2Y2 nucleotide receptor up-regulation in submandibular gland cells from the NOD.B10 mouse model of Sjogren’s syndrome. Arch Oral Biol 50(6):533–40

    Article  CAS  PubMed  Google Scholar 

  108. Ahn JS, Camden JM, Schrader AM, Redman RS, Turner JT (2000) Reversible regulation of P2Y(2) nucleotide receptor expression in the duct-ligated rat submandibular gland. Am J Physiol Cell Physiol 279(2):C286–C294

    Article  CAS  PubMed  Google Scholar 

  109. Nowbar AN, Gitto M, Howard JP, Francis DP, Al-Lamee R (2019) Mortality from ischemic heart disease. Circ Cardiovasc Qual Outcomes 12(6):e005375

    Article  PubMed  PubMed Central  Google Scholar 

  110. Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352(16):1685–1695

    Article  CAS  PubMed  Google Scholar 

  111. Chen X, Qian S, Hoggatt A, Tang H, Hacker TA, Obukhov AG et al (2017) Endothelial cell-specific deletion of P2Y2 receptor promotes plaque stability in atherosclerosis-susceptible ApoE-null mice. Arterioscler Thromb Vasc Biol 37(1):75–83

    Article  CAS  PubMed  Google Scholar 

  112. Hochhauser E, Cohen R, Waldman M, Maksin A, Isak A, Aravot D et al (2013) P2Y2 receptor agonist with enhanced stability protects the heart from ischemic damage in vitro and in vivo. Purinergic Signal 9(4):633–642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Khalafalla FG, Greene S, Khan H, Ilves K, Monsanto MM, Alvarez R Jr et al (2017) P2Y2 nucleotide receptor prompts human cardiac progenitor cell activation by modulating hippo signaling. Circ Res 121(11):1224–1236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Ritchie H, Roser M (2017) Obesity. OurWorldInData.org. https://ourworldindata.org/obesity. Accessed 11 Aug 2022

  115. Powell-Wiley TM, Poirier P, Burke LE, Despres JP, Gordon-Larsen P, Lavie CJ et al (2021) Obesity and cardiovascular eisease: a scientific statement from the American Heart Association. Circulation 143(21):e984–e1010

    Article  PubMed  PubMed Central  Google Scholar 

  116. Franks PW, McCarthy MI (2016) Exposing the exposures responsible for type 2 diabetes and obesity. Science 354(6308):69–73

    Article  CAS  PubMed  Google Scholar 

  117. Kishore B, Zhang Y, Ecelbarger C (2018) US Department of Veterans Affairs. Methods for treating diet-induced obesity by decreasing and inhibiting P2Y2 purinergic receptor expression or activity. US10024846B2

  118. Zhang Y, Ecelbarger CM, Lesniewski LA, Muller CE, Kishore BK (2020) P2Y2 receptor promotes high-fat diet-induced obesity. Front Endocrinol (Lausanne) 11:341

    Article  PubMed  Google Scholar 

  119. Dusabimana T, Park EJ, Je J, Jeong K, Yun SP, Kim HJ et al (2021) P2Y2R deficiency ameliorates hepatic steatosis by reducing lipogenesis and enhancing fatty acid β-oxidation through AMPK and PGC-1α induction in high-fat diet-fed mice. Int J Mol Sci 22(11):5528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Li W, Wei S, Liu C, Song M, Wu H, Yang Y (2016) Regulation of the osteogenic and adipogenic differentiation of bone marrow-derived stromal cells by extracellular uridine triphosphate: the role of P2Y2 receptor and ERK1/2 signaling. Int J Mol Med 37(1):63–73

    Article  CAS  PubMed  Google Scholar 

  121. Chang JT (2020) Pathophysiology of inflammatory bowel diseases. N Engl J Med 383(27):2652–2664

    Article  CAS  PubMed  Google Scholar 

  122. Grbic DM, Degagne E, Langlois C, Dupuis AA, Gendron FP (2008) Intestinal inflammation increases the expression of the P2Y6 receptor on epithelial cells and the release of CXC chemokine ligand 8 by UDP. J Immunol 180(4):2659–2668

    Article  CAS  PubMed  Google Scholar 

  123. Guzman J, Yu JG, Suntres Z, Bozarov A, Cooke H, Javed N et al (2006) ADOA3R as a therapeutic target in experimental colitis: proof by validated high-density oligonucleotide microarray analysis. Inflamm Bowel Dis 12(8):766–789

    Article  PubMed  Google Scholar 

  124. Degagne E, Degrandmaison J, Grbic DM, Vinette V, Arguin G, Gendron FP (2013) P2Y2 receptor promotes intestinal microtubule stabilization and mucosal re-epithelization in experimental colitis. J Cell Physiol 228(1):99–109

    Article  CAS  PubMed  Google Scholar 

  125. Stander S (2021) Atopic Dermatitis. N Engl J Med 384(12):1136–1143

    Article  PubMed  Google Scholar 

  126. Riteau N, Gasse P, Fauconnier L, Gombault A, Couegnat M, Fick L et al (2010) Extracellular ATP is a danger signal activating P2X7 receptor in lung inflammation and fibrosis. Am J Respir Crit Care Med 182(6):774–783

    Article  CAS  PubMed  Google Scholar 

  127. Xu H, Wang M, Li Y, Shi M, Wang Z, Cao C et al (2022) Blocking connexin 43 and its promotion of ATP release from renal tubular epithelial cells ameliorates renal fibrosis. Cell Death Dis 13(5):511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Lu D, Soleymani S, Madakshire R, Insel PA (2012) ATP released from cardiac fibroblasts via connexin hemichannels activates profibrotic P2Y2 receptors. FASEB J 26(6):2580–2591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Braun OO, Lu D, Aroonsakool N, Insel PA (2010) Uridine triphosphate (UTP) induces profibrotic responses in cardiac fibroblasts by activation of P2Y2 receptors. J Mol Cell Cardiol 49(3):362–369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Chen M, Chen H, Gu Y, Sun P, Sun J, Yu H et al (2021) P2Y2 promotes fibroblasts activation and skeletal muscle fibrosis through AKT, ERK, and PKC. BMC Musculoskelet Disord 22(1):680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Jin H, Seo J, Eun SY, Joo YN, Park SW, Lee JH et al (2014) P2Y2 R activation by nucleotides promotes skin wound-healing process. Exp Dermatol 23(7):480–485

    Article  CAS  PubMed  Google Scholar 

  132. Tomasek JJ, Vaughan MB, Kropp BP, Gabbiani G, Martin MD, Haaksma CJ et al (2006) Contraction of myofibroblasts in granulation tissue is dependent on Rho/Rho kinase/myosin light chain phosphatase activity. Wound Repair Regen 14(3):313–320

    Article  PubMed  Google Scholar 

  133. Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA (2002) Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 3(5):349–363

    Article  CAS  PubMed  Google Scholar 

  134. Parizi M, Howard EW, Tomasek JJ (2000) Regulation of LPA-promoted myofibroblast contraction: role of Rho, myosin light chain kinase, and myosin light chain phosphatase. Exp Cell Res 254(2):210–220

    Article  CAS  PubMed  Google Scholar 

  135. Liu F, Lagares D, Choi KM, Stopfer L, Marinkovic A, Vrbanac V et al (2015) Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis. Am J Physiol Lung Cell Mol Physiol 308(4):L344–L357

    Article  CAS  PubMed  Google Scholar 

  136. Kagan HM, Li W (2003) Lysyl oxidase: properties, specificity, and biological roles inside and outside of the cell. J Cell Biochem 88(4):660–672

    Article  CAS  PubMed  Google Scholar 

  137. Joo YN, Jin H, Eun SY, Park SW, Chang KC, Kim HJ (2014) P2Y2R activation by nucleotides released from the highly metastatic breast cancer cell MDA-MB-231 contributes to pre-metastatic niche formation by mediating lysyl oxidase secretion, collagen crosslinking, and monocyte recruitment. Oncotarget 5(19):9322–9334

    Article  PubMed  PubMed Central  Google Scholar 

  138. Hong KO, Kim JH, Hong JS, Yoon HJ, Lee JI, Hong SP et al (2009) Inhibition of Akt activity induces the mesenchymal-to-epithelial reverting transition with restoring E-cadherin expression in KB and KOSCC-25B oral squamous cell carcinoma cells. J Exp Clin Cancer Res 28:28

    Article  PubMed  PubMed Central  Google Scholar 

  139. Cressman VL, Lazarowski E, Homolya L, Boucher RC, Koller BH, Grubb BR (1999) Effect of loss of P2Y(2) receptor gene expression on nucleotide regulation of murine epithelial Cl(-) transport. J Biol Chem 274(37):26461–26468

    Article  CAS  PubMed  Google Scholar 

  140. Faria D, Schreiber R, Kunzelmann K (2009) CFTR is activated through stimulation of purinergic P2Y2 receptors. Pflugers Arch 457(6):1373–1380

    Article  CAS  PubMed  Google Scholar 

  141. Denton CP, Khanna D (2017) Systemic sclerosis. Lancet 390(10103):1685–1699

    Article  PubMed  Google Scholar 

  142. Kadono T, Kikuchi K, Ihn H, Takehara K, Tamaki K (1998) Increased production of interleukin 6 and interleukin 8 in scleroderma fibroblasts. J Rheumatol 25(2):296–301

    CAS  PubMed  Google Scholar 

  143. De Lauretis A, Sestini P, Pantelidis P, Hoyles R, Hansell DM, Goh NS et al (2013) Serum interleukin 6 is predictive of early functional decline and mortality in interstitial lung disease associated with systemic sclerosis. J Rheumatol 40(4):435–446

    Article  PubMed  Google Scholar 

  144. Kitaba S, Murota H, Terao M, Azukizawa H, Terabe F, Shima Y et al (2012) Blockade of interleukin-6 receptor alleviates disease in mouse model of scleroderma. Am J Pathol 180(1):165–176

    Article  CAS  PubMed  Google Scholar 

  145. Lederer DJ, Martinez FJ (2018) Idiopathic pulmonary fibrosis. N Engl J Med 378(19):1811–1823

    Article  CAS  PubMed  Google Scholar 

  146. Noble PW, Albera C, Bradford WZ, Costabel U, du Bois RM, Fagan EA et al (2016) Pirfenidone for idiopathic pulmonary fibrosis: analysis of pooled data from three multinational phase 3 trials. Eur Respir J 47(1):243–253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U et al (2014) Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 370(22):2071–2082

    Article  PubMed  Google Scholar 

  148. Richeldi L, Azuma A, Cottin V, Hesslinger C, Stowasser S, Valenzuela C et al (2022) Trial of a preferential phosphodiesterase 4B inhibitor for idiopathic pulmonary fibrosis. N Engl J Med 386(23):2178–2187

    Article  CAS  PubMed  Google Scholar 

  149. Muller T, Fay S, Vieira RP, Karmouty-Quintana H, Cicko S, Ayata K et al (2017) The purinergic receptor subtype P2Y2 mediates chemotaxis of neutrophils and fibroblasts in fibrotic lung disease. Oncotarget 8(22):35962–35972

    Article  PubMed  PubMed Central  Google Scholar 

  150. Burnstock G, Evans LC, Bailey MA (2014) Purinergic signalling in the kidney in health and disease. Purinergic Signal 10(1):71–101

    Article  CAS  PubMed  Google Scholar 

  151. Menzies RI, Tam FW, Unwin RJ, Bailey MA (2017) Purinergic signaling in kidney disease. Kidney Int 91(2):315–323

    Article  CAS  PubMed  Google Scholar 

  152. Verschuren EHJ, Rigalli JP, Castenmiller C, Rohrbach MU, Bindels RJM, Peters DJM et al (2020) Pannexin-1 mediates fluid shear stress-sensitive purinergic signaling and cyst growth in polycystic kidney disease. FASEB J 34(5):6382–6398

    Article  CAS  PubMed  Google Scholar 

  153. Satoskar AA, Parikh SV, Nadasdy T (2020) Epidemiology, pathogenesis, treatment and outcomes of infection-associated glomerulonephritis. Nat Rev Nephrol 16(1):32–50

    Article  CAS  PubMed  Google Scholar 

  154. Anders HJ, Saxena R, Zhao MH, Parodis I, Salmon JE, Mohan C (2020) Lupus nephritis. Nat Rev Dis Primers 6(1):7

    Article  PubMed  Google Scholar 

  155. DeVrieze BW, Hurley JA (2022) Goodpasture syndrome. StatPearls, Treasure Island (FL)

    Google Scholar 

  156. Lai KN, Tang SC, Schena FP, Novak J, Tomino Y, Fogo AB et al (2016) IgA nephropathy. Nat Rev Dis Primers 2:16001

    Article  PubMed  Google Scholar 

  157. Bossini N, Savoldi S, Franceschini F, Mombelloni S, Baronio M, Cavazzana I et al (2001) Clinical and morphological features of kidney involvement in primary Sjogren’s syndrome. Nephrol Dial Transplant 16(12):2328–2336

    Article  CAS  PubMed  Google Scholar 

  158. Maripuri S, Grande JP, Osborn TG, Fervenza FC, Matteson EL, Donadio JV et al (2009) Renal involvement in primary Sjogren’s syndrome: a clinicopathologic study. Clin J Am Soc Nephrol 4(9):1423–1431

    Article  PubMed  PubMed Central  Google Scholar 

  159. Centers for Disease Control and Prevention (2021) Chronic kidney disease in the United States, 2021. US Department of Health and Human Services, Centers for Disease Control and Prevention, Atlanta

    Google Scholar 

  160. Rennert L, Zschiedrich S, Sandner L, Hartleben B, Cicko S, Ayata CK et al (2018) P2Y2R signaling is involved in the onset of glomerulonephritis. Front Immunol 9:1589

    Article  PubMed  PubMed Central  Google Scholar 

  161. Remuzzi G, Schieppati A, Ruggenenti P (2002) Clinical practice. Nephropathy in patients with type 2 diabetes. N Engl J Med 346(15):1145–51

    Article  PubMed  Google Scholar 

  162. Furman BL (2021) Streptozotocin-induced diabetic models in mice and rats. Curr Protoc 1(4):e78

    CAS  PubMed  Google Scholar 

  163. Tan RZ, Zhong X, Li JC, Zhang YW, Yan Y, Liao Y et al (2019) An optimized 5/6 nephrectomy mouse model based on unilateral kidney ligation and its application in renal fibrosis research. Ren Fail 41(1):555–566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Kim H, Dusabimana T, Kim SR, Je J, Jeong K, Kang MC et al (2018) Supplementation of Abelmoschus manihot ameliorates diabetic nephropathy and hepatic steatosis by activating autophagy in mice. Nutrients 10(11):1703

    Article  PubMed  PubMed Central  Google Scholar 

  165. Dusabimana T, Kim SR, Park EJ, Je J, Jeong K, Yun SP et al (2020) P2Y2R contributes to the development of diabetic nephropathy by inhibiting autophagy response. Mol Metab 42:101089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Koch EAT, Nakhoul R, Nakhoul F, Nakhoul N (2020) Autophagy in diabetic nephropathy: a review. Int Urol Nephrol 52(9):1705–1712

    Article  CAS  PubMed  Google Scholar 

  167. Zaparte A, Cappellari AR, Brandao CA, de Souza JB, Borges TJ, Kist LW et al (2021) P2Y2 receptor activation promotes esophageal cancer cells proliferation via ERK1/2 pathway. Eur J Pharmacol 891:173687

    Article  CAS  PubMed  Google Scholar 

  168. Leemans CR, Snijders PJF, Brakenhoff RH (2018) The molecular landscape of head and neck cancer. Nat Rev Cancer 18(5):269–282

    Article  CAS  PubMed  Google Scholar 

  169. Chow LQM (2020) Head and Neck Cancer. N Engl J Med 382(1):60–72

    Article  CAS  PubMed  Google Scholar 

  170. Taberna M, Oliva M, Mesia R (2019) Cetuximab-containing combinations in locally advanced and recurrent or metastatic head and neck squamous cell carcinoma. Front Oncol 9:383

    Article  PubMed  PubMed Central  Google Scholar 

  171. Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y et al (2020) Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med 382(1):41–50

    Article  CAS  PubMed  Google Scholar 

  172. Soulieres D, Senzer NN, Vokes EE, Hidalgo M, Agarwala SS, Siu LL (2004) Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol 22(1):77–85

    Article  CAS  PubMed  Google Scholar 

  173. Cassell A, Grandis JR (2010) Investigational EGFR-targeted therapy in head and neck squamous cell carcinoma. Expert Opin Investig Drugs 19(6):709–722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Stewart JS, Cohen EE, Licitra L, Van Herpen CM, Khorprasert C, Soulieres D et al (2009) Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected]. J Clin Oncol 27(11):1864–1871

    Article  CAS  PubMed  Google Scholar 

  175. Grandis JR, Tweardy DJ (1993) Elevated levels of transforming growth factor α and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res 53(15):3579–3584

    CAS  PubMed  Google Scholar 

  176. Vermorken JB, Herbst RS, Leon X, Amellal N, Baselga J (2008) Overview of the efficacy of cetuximab in recurrent and/or metastatic squamous cell carcinoma of the head and neck in patients who previously failed platinum-based therapies. Cancer 112(12):2710–2719

    Article  CAS  PubMed  Google Scholar 

  177. Quesnelle KM, Wheeler SE, Ratay MK, Grandis JR (2012) Preclinical modeling of EGFR inhibitor resistance in head and neck cancer. Cancer Biol Ther 13(10):935–945

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Burnstock G, Vaughn B, Robson SC (2014) Purinergic signalling in the liver in health and disease. Purinergic Signal 10(1):51–70

    Article  CAS  PubMed  Google Scholar 

  179. Xie R, Xu J, Wen G, Jin H, Liu X, Yang Y et al (2014) The P2Y2 nucleotide receptor mediates the proliferation and migration of human hepatocellular carcinoma cells induced by ATP. J Biol Chem 289(27):19137–19149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Ayata CK, Ganal SC, Hockenjos B, Willim K, Vieira RP, Grimm M et al (2012) Purinergic P2Y(2) receptors promote neutrophil infiltration and hepatocyte death in mice with acute liver injury. Gastroenterology. 143(6):1620–9.e4

    Article  CAS  PubMed  Google Scholar 

  181. Velazquez-Miranda E, Molina-Aguilar C, Gonzalez-Gallardo A, Vazquez-Martinez O, Diaz-Munoz M, Vazquez-Cuevas FG (2020) Increased purinergic responses dependent on P2Y2 receptors in hepatocytes from CCl4-treated fibrotic mice. Int J Mol Sci 21(7):2305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Tackett BC, Sun H, Mei Y, Maynard JP, Cheruvu S, Mani A et al (2014) P2Y2 purinergic receptor activation is essential for efficient hepatocyte proliferation in response to partial hepatectomy. Am J Physiol Gastrointest Liver Physiol 307(11):G1073–G1087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Schulien I, Hockenjos B, van Marck V, Ayata CK, Follo M, Thimme R et al (2020) Extracellular ATP and purinergic P2Y2 receptor signaling promote liver tumorigenesis in mice by exacerbating DNA damage. Cancer Res 80(4):699–708

    Article  CAS  PubMed  Google Scholar 

  184. Stepniak E, Ricci R, Eferl R, Sumara G, Sumara I, Rath M et al (2006) c-Jun/AP-1 controls liver regeneration by repressing p53/p21 and p38 MAPK activity. Genes Dev 20(16):2306–2314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Sarantis P, Koustas E, Papadimitropoulou A, Papavassiliou AG, Karamouzis MV (2020) Pancreatic ductal adenocarcinoma: treatment hurdles, tumor microenvironment and immunotherapy. World J Gastrointest Oncol 12(2):173–181

    Article  PubMed  PubMed Central  Google Scholar 

  186. Steinle AU, Weidenbach H, Wagner M, Adler G, Schmid RM (1999) NF-kB/Rel activation in cerulein pancreatitis. Gastroenterology 116(2):420–430

    Article  CAS  PubMed  Google Scholar 

  187. Ferreira RMM, Sancho R, Messal HA, Nye E, Spencer-Dene B, Stone RK et al (2017) Duct- and acinar-derived pancreatic ductal adenocarcinomas show distinct tumor progression and marker expression. Cell Rep 21(4):966–978

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Koch AE, Halloran MM, Haskell CJ, Shah MR, Polverini PJ (1995) Angiogenesis mediated by soluble forms of E-selectin and vascular cell adhesion molecule-1. Nature 376(6540):517–519

    Article  CAS  PubMed  Google Scholar 

  189. Gho YS, Kim PN, Li HC, Elkin M, Kleinman HK (2001) Stimulation of tumor growth by human soluble intercellular adhesion molecule-1. Cancer Res 61(10):4253–4257

    CAS  PubMed  Google Scholar 

  190. Jin H, Eun SY, Lee JS, Park SW, Lee JH, Chang KC et al (2014) P2Y2 receptor activation by nucleotides released from highly metastatic breast cancer cells increases tumor growth and invasion via crosstalk with endothelial cells. Breast Cancer Res 16(5):R77

    Article  PubMed  PubMed Central  Google Scholar 

  191. Li WH, Qiu Y, Zhang HQ, Liu Y, You JF, Tian XX et al (2013) P2Y2 receptor promotes cell invasion and metastasis in prostate cancer cells. Br J Cancer 109(6):1666–1675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Weisman GA, Camden JM, Peterson TS, Ajit D, Woods LT, Erb L (2012) P2 receptors for extracellular nucleotides in the central nervous system: role of P2X7 and P2Y(2) receptor interactions in neuroinflammation. Mol Neurobiol 46(1):96–113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Franke H, Krugel U, Grosche J, Heine C, Hartig W, Allgaier C et al (2004) P2Y receptor expression on astrocytes in the nucleus accumbens of rats. Neuroscience 127(2):431–441

    Article  CAS  PubMed  Google Scholar 

  194. Rodriguez-Zayas AE, Torrado AI, Miranda JD (2010) P2Y2 receptor expression is altered in rats after spinal cord injury. Int J Dev Neurosci 28(6):413–421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Franke H, Illes P (2006) Involvement of P2 receptors in the growth and survival of neurons in the CNS. Pharmacol Ther 109(3):297–324

    Article  CAS  PubMed  Google Scholar 

  196. Inoue K (2008) Purinergic systems in microglia. Cell Mol Life Sci 65(19):3074–3080

    Article  CAS  PubMed  Google Scholar 

  197. Peterson TS, Camden JM, Wang Y, Seye CI, Wood WG, Sun GY et al (2010) P2Y2 nucleotide receptor-mediated responses in brain cells. Mol Neurobiol 41(2–3):356–366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Chen Y, Yao Y, Sumi Y, Li A, To UK, Elkhal A et al (2010) Purinergic signaling: a fundamental mechanism in neutrophil activation. Sci Signal. 3(125):ra45

    Article  PubMed  PubMed Central  Google Scholar 

  199. Messlinger K, Russo AF (2019) Current understanding of trigeminal ganglion structure and function in headache. Cephalalgia 39(13):1661–1674

    Article  PubMed  Google Scholar 

  200. Ceruti S, Villa G, Fumagalli M, Colombo L, Magni G, Zanardelli M et al (2011) Calcitonin gene-related peptide-mediated enhancement of purinergic neuron/glia communication by the algogenic factor bradykinin in mouse trigeminal ganglia from wild-type and R192Q Cav2.1 Knock-in mice: implications for basic mechanisms of migraine pain. J Neurosci. 31(10):3638–49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Long JM, Holtzman DM (2019) Alzheimer disease: an update on pathobiology and treatment strategies. Cell 179(2):312–339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Onuska KM (2020) The dual role of microglia in the progression of Alzheimer’s disease. J Neurosci 40(8):1608–1610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Passamonti L, Tsvetanov KA, Jones PS, Bevan-Jones WR, Arnold R, Borchert RJ et al (2019) Neuroinflammation and functional connectivity in Alzheimer’s disease: interactive influences on cognitive performance. J Neurosci 39(36):7218–7226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Hansen DV, Hanson JE, Sheng M (2018) Microglia in Alzheimer’s disease. J Cell Biol 217(2):459–472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Yeh FL, Wang Y, Tom I, Gonzalez LC, Sheng M (2016) TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-beta by microglia. Neuron 91(2):328–340

    Article  CAS  PubMed  Google Scholar 

  206. Sosna J, Philipp S, Albay R 3rd, Reyes-Ruiz JM, Baglietto-Vargas D, LaFerla FM et al (2018) Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, neuritic plaque deposition and pre-fibrillar oligomers in 5XFAD mouse model of Alzheimer’s disease. Mol Neurodegener 13(1):11

    Article  PubMed  PubMed Central  Google Scholar 

  207. Ng A, Tam WW, Zhang MW, Ho CS, Husain SF, McIntyre RS et al (2018) IL-1beta, IL-6, TNF-α and CRP in elderly patients with depression or Alzheimer’s disease: systematic review and meta-analysis. Sci Rep 8(1):12050

    Article  PubMed  PubMed Central  Google Scholar 

  208. Kim HJ, Ajit D, Peterson TS, Wang Y, Camden JM, Gibson Wood W et al (2012) Nucleotides released from Aβ1-42-treated microglial cells increase cell migration and Aβ1-42 uptake through P2Y2 receptor activation. J Neurochem 121(2):228–238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Ajit D, Woods LT, Camden JM, Thebeau CN, El-Sayed FG, Greeson GW et al (2014) Loss of P2Y2 nucleotide receptors enhances early pathology in the TgCRND8 mouse model of Alzheimer’s disease. Mol Neurobiol 49(2):1031–1042

    Article  CAS  PubMed  Google Scholar 

  210. Eberhardt N, Bergero G, Mazzocco Mariotta YL, Aoki MP (2022) Purinergic modulation of the immune response to infections. Purinergic Signal 18(1):93–113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Vanderstocken G, Van de Paar E, Robaye B, di Pietrantonio L, Bondue B, Boeynaems JM et al (2012) Protective role of P2Y2 receptor against lung infection induced by pneumonia virus of mice. PLoS ONE 7(11):e50385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Chen B (2019) Molecular mechanism of HIV-1 entry. Trends Microbiol 27(10):878–891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Barmania F, Pepper MS (2013) C-C chemokine receptor type five (CCR5): an emerging target for the control of HIV infection. Appl Transl Genom 2:3–16

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Bleul CC, Wu L, Hoxie JA, Springer TA, Mackay CR (1997) The HIV coreceptors CXCR4 and CCR5 are differentially expressed and regulated on human T lymphocytes. Proc Natl Acad Sci U S A 94(5):1925–1930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Seror C, Melki MT, Subra F, Raza SQ, Bras M, Saidi H et al (2011) Extracellular ATP acts on P2Y2 purinergic receptors to facilitate HIV-1 infection. J Exp Med 208(9):1823–1834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. D’Amico D, Valdebenito S, Eugenin EA (2021) The role of pannexin-1 channels and extracellular ATP in the pathogenesis of the human immunodeficiency virus. Purinergic Signal 17(4):563–576

    Article  PubMed  PubMed Central  Google Scholar 

  217. Zhang M, Piskuric NA, Vollmer C, Nurse CA (2012) P2Y2 receptor activation opens pannexin-1 channels in rat carotid body type II cells: potential role in amplifying the neurotransmitter ATP. J Physiol 590(17):4335–4350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Horioka M, Ceraudo E, Lorenzen E, Sakmar TP, Huber T (2021) Purinergic receptors crosstalk with CCR5 to amplify Ca2+ signaling. Cell Mol Neurobiol 41(5):1085–1101

    Article  CAS  PubMed  Google Scholar 

  219. Vaheri A, Strandin T, Hepojoki J, Sironen T, Henttonen H, Makela S et al (2013) Uncovering the mysteries of hantavirus infections. Nat Rev Microbiol 11(8):539–550

    Article  CAS  PubMed  Google Scholar 

  220. Raymond T, Gorbunova E, Gavrilovskaya IN, Mackow ER (2005) Pathogenic hantaviruses bind plexin-semaphorin-integrin domains present at the apex of inactive, bent αvβ3 integrin conformers. Proc Natl Acad Sci U S A 102(4):1163–1168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Bondu V, Wu C, Cao W, Simons PC, Gillette J, Zhu J et al (2017) Low-affinity binding in cis to P2Y2R mediates force-dependent integrin activation during hantavirus infection. Mol Biol Cell 28(21):2887–2903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Bondu V, Bitting C, Poland VL, Hanson JA, Harkins MS, Lathrop S et al (2018) Upregulation of P2Y2R, active uPA, and PAI-1 are essential components of hantavirus cardiopulmonary syndrome. Front Cell Infect Microbiol 8:169

    Article  PubMed  PubMed Central  Google Scholar 

  223. Sévigny J, Mabrouka S (2018) Université Laval. Treatment of inflammatory bowel disease. WO2018058246A1

  224. Gabrilovich DI (2020) The Wistare Institute of Anatomy and Biology. Compositions and methods for altering neutrophil migration and metastasis. WO2020081452

  225. Conroy S, Kindon ND, Glenn J, Stoddart LA, Lewis RJ, Hill SJ et al (2018) Synthesis and evaluation of the first fluorescent antagonists of the human P2Y2 receptor based on AR-C118925. J Med Chem 61(7):3089–3113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by National Institute of Dental and Craniofacial Research grants R01DE007389 (GAW), R01DE023342 (GAW), R01DE029833 (GAW, SC, KJJ), and R21AR079693 (SC) and a Sjögren’s Foundation grant (KJJ, SC). KMF is supported by a University of Missouri Life Sciences Fellowship and the Wayne L. Ryan Foundation Fellowship from the Ryan Foundation.

Author information

Authors and Affiliations

  1. Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, USA

    Kimberly J. Jasmer, Kevin Muñoz Forti, Lucas T. Woods & Gary A. Weisman

  2. Department of Biochemistry, University of Missouri, Columbia, MO, USA

    Kimberly J. Jasmer, Kevin Muñoz Forti, Lucas T. Woods & Gary A. Weisman

  3. Department of Oral and Maxillofacial Diagnostic Sciences, Center for Orphaned Autoimmune Disorders, University of Florida College of Dentistry, Gainesville, FL, USA

    Seunghee Cha

Authors
  1. Kimberly J. Jasmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kevin Muñoz Forti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lucas T. Woods
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Seunghee Cha
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gary A. Weisman
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors developed the idea for this review. KJJ and KMF performed literature searches, KJJ and KMF drafted the manuscript, and KJJ, LTW, SC, and GAW critically revised the draft.

Corresponding author

Correspondence to Gary A. Weisman.

Ethics declarations

Ethical approval

Not applicable.

Informed consent

Not applicable.

Competing interests

The authors declare no competing interests.

Conflicts of interest

The authors declare no conflicts of interest.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jasmer, K.J., Muñoz Forti, K., Woods, L.T. et al. Therapeutic potential for P2Y2 receptor antagonism. Purinergic Signalling 19, 401–420 (2023). https://doi.org/10.1007/s11302-022-09900-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11302-022-09900-3

Keywords

Search

Navigation