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ADP receptor P2Y13 induce apoptosis in pancreatic β-cells

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Abstract

Pancreatic β-cell loss represents a key factor in the pathogenesis of diabetes. Since the influence of purinergic signaling in β-cell apoptosis has not been much investigated, we examined the role of the ADP receptor P2Y13 using the pancreatic insulinoma-cell line MIN6c4 as a model system. Real time-PCR revealed high expression of the ADP receptors P2Y1 and P2Y13. Adding the ADP analogue, 2MeSADP, to MIN6c4 cells induced calcium influx/mobilization and inhibition of cAMP production by activation of P2Y1 and P2Y13, respectively. 2MeSADP reduced cell proliferation and increased Caspase-3 activity; both these effects could be fully reversed by the P2Y13 receptor antagonist MRS2211. We further discovered that blocking the P2Y13 receptor results in enhanced ERK1/2, Akt/PKB and CREB phosphorylation mechanisms involved in β-cell survival. These results indicate that P2Y13 is a proapoptotic receptor in β-cells as the P2Y13 receptor antagonist MRS2211 is able to protect the cells from ADP induced apoptosis.

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References

  1. Anderson CD, Pierce J, Nicoud IB, Belous AE, Jones CM, Chari RS (2007) Purinergic receptor antagonism prevents cold preservation-induced cell death independent of cellular ATP levels. J Surg Res 141:234–240

    Article  CAS  PubMed  Google Scholar 

  2. Parodi J, Flores C, Aguayo C, Rudolph MI, Casanello P, Sobrevia L (2002) Inhibition of nitrobenzylthioinosine-sensitive adenosine transport by elevated d-glucose involves activation of P2Y2 purinoceptors in human umbilical vein endothelial cells. Circ Res 90:570–577

    Article  CAS  PubMed  Google Scholar 

  3. Nilsson J, Nilsson LM, Chen YW, Molkentin JD, Erlinge D, Gomez MF (2006) High glucose activates nuclear factor of activated T cells in native vascular smooth muscle. Arterioscler Thromb Vasc Biol 26:794–800

    Article  CAS  PubMed  Google Scholar 

  4. Solini A, Iacobini C, Ricci C, Chiozzi P, Amadio L, Pricci F, Di MU, Di VF, Pugliese G (2005) Purinergic modulation of mesangial extracellular matrix production: role in diabetic and other glomerular diseases. Kidney Int 67:875–885

    Article  CAS  PubMed  Google Scholar 

  5. Hazama A, Hayashi S, Okada Y (1998) Cell surface measurements of ATP release from single pancreatic beta cells using a novel biosensor technique. Pflugers Arch 437:31–35

    Article  CAS  PubMed  Google Scholar 

  6. Chen YJ, Hsu KW, Chen YL (2006) Acute glucose overload potentiates nitric oxide production in lipopolysaccharide-stimulated macrophages: the role of purinergic receptor activation. Cell Biol Int 30:817–822

    Article  CAS  PubMed  Google Scholar 

  7. Novak I (2008) Purinergic receptors in the endocrine and exocrine pancreas. Purinergic Signal 4:237–253

    Article  CAS  PubMed  Google Scholar 

  8. Burnstock G (2006) Purinergic signalling. Br J Pharmacol 147(Suppl 1):S172–S181

    Article  CAS  PubMed  Google Scholar 

  9. Alvarado-Castillo C, Harden TK, Boyer JL (2005) Regulation of P2Y1 receptor-mediated signaling by the ectonucleoside triphosphate diphosphohydrolase isozymes NTPDase1 and NTPDase2. Mol Pharmacol 67:114–122

    Article  CAS  PubMed  Google Scholar 

  10. Fredholm BB (2007) Adenosine, an endogenous distress signal, modulates tissue damage and repair. Cell Death Differ 14:1315–1323

    Article  CAS  PubMed  Google Scholar 

  11. Loubatieres-Mariani MM, Chapal J, Lignon F, Valette G (1979) Structural specificity of nucleotides for insulin secretory action from the isolated perfused rat pancreas. Eur J Pharmacol 59:277–286

    Article  CAS  PubMed  Google Scholar 

  12. Bertrand G, Chapal J, Puech R, Loubatieres-Mariani MM (1991) Adenosine-5′-O-(2-thiodiphosphate) is a potent agonist at P2 purinoceptors mediating insulin secretion from perfused rat pancreas. Br J Pharmacol 102:627–630

    CAS  PubMed  Google Scholar 

  13. Fernandez-Alvarez J, Hillaire-Buys D, Loubatieres-Mariani MM, Gomis R, Petit P (2001) P2 receptor agonists stimulate insulin release from human pancreatic islets. Pancreas 22:69–71

    Article  CAS  PubMed  Google Scholar 

  14. Petit P, Bertrand G, Schmeer W, Henquin JC (1989) Effects of extracellular adenine nucleotides on the electrical, ionic and secretory events in mouse pancreatic beta-cells. Br J Pharmacol 98:875–882

    CAS  PubMed  Google Scholar 

  15. Poulsen CR, Bokvist K, Olsen HL, Hoy M, Capito K, Gilon P, Gromada J (1999) Multiple sites of purinergic control of insulin secretion in mouse pancreatic beta-cells. Diabetes 48:2171–2181

    Article  CAS  PubMed  Google Scholar 

  16. Hellman B, Dansk H, Grapengiesser E (2004) Pancreatic beta-cells communicate via intermittent release of ATP. Am J Physiol Endocrinol Metab 286:E759–E765

    Article  CAS  PubMed  Google Scholar 

  17. Blachier F, Malaisse WJ (1988) Effect of exogenous ATP upon inositol phosphate production, cationic fluxes and insulin release in pancreatic islet cells. Biochim Biophys Acta 970:222–229

    Article  CAS  PubMed  Google Scholar 

  18. Hillaire-Buys D, Chapal J, Bertrand G, Petit P, Loubatieres-Mariani MM (1994) Purinergic receptors on insulin-secreting cells. Fundam Clin Pharmacol 8:117–127

    Article  CAS  PubMed  Google Scholar 

  19. Mathis D, Vence L, Benoist C (2001) beta-Cell death during progression to diabetes. Nature 414:792–798

    Article  CAS  PubMed  Google Scholar 

  20. de Koning EJ, Bonner-Weir S, Rabelink TJ (2008) Preservation of beta-cell function by targeting beta-cell mass. Trends Pharmacol Sci 29:218–227

    Article  PubMed  Google Scholar 

  21. Kim JW, Ko SH, Cho JH, Sun C, Hong OK, Lee SH, Kim JH, Lee KW, Kwon HS, Lee JM, Song KH, Son HY, Yoon KH (2008) Loss of beta-cells with fibrotic islet destruction in type 2 diabetes mellitus. Front Biosci 13:6022–6033

    Article  CAS  PubMed  Google Scholar 

  22. Santini E, Cuccato S, Madec S, Chimenti D, Ferrannini E, Solini A (2009) Extracellular ATP modulates insulin secretion via functionally active purinergic receptors of X and Y subtype. Endocrinology (in press)

  23. Franke H, Sauer C, Rudolph C, Krugel U, Hengstler JG, Illes P (2008) P2 receptor-mediated stimulation of the PI3-K/Akt-pathway in vivo. Glia (in press)

  24. Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29:e45

    Article  CAS  PubMed  Google Scholar 

  25. Burnstock G (2006) Historical review: ATP as a neurotransmitter. Trends Pharmacol Sci 27:166–176

    Article  CAS  PubMed  Google Scholar 

  26. Lugo-Garcia L, Filhol R, Lajoix AD, Gross R, Petit P, Vignon J (2007) Expression of purinergic P2Y receptor subtypes by INS-1 insulinoma beta-cells: a molecular and binding characterization. Eur J Pharmacol 568:54–60

    Article  CAS  PubMed  Google Scholar 

  27. Hauge-Evans AC, Squires PE, Belin VD, Roderigo-Milne H, Ramracheya RD, Persaud SJ, Jones PM (2002) Role of adenine nucleotides in insulin secretion from MIN6 pseudoislets. Mol Cell Endocrinol 191:167–176

    Article  CAS  PubMed  Google Scholar 

  28. Wada T, Penninger JM (2004) Mitogen-activated protein kinases in apoptosis regulation. Oncogene 23:2838–2849

    Article  CAS  PubMed  Google Scholar 

  29. Costes S, Vandewalle B, Tourrel-Cuzin C, Broca C, Linck N, Bertrand G, Kerr-Conte J, Portha B, Pattou F, Bockaert J, Dalle S (2009) Degradation of cAMP-responsive element-binding protein by the ubiquitin-proteasome pathway contributes to glucotoxicity in beta-cells and human pancreatic islets. Diabetes 58:1105–1115

    Article  CAS  PubMed  Google Scholar 

  30. Jhala US, Canettieri G, Screaton RA, Kulkarni RN, Krajewski S, Reed J, Walker J, Lin X, White M, Montminy M (2003) cAMP promotes pancreatic beta-cell survival via CREB-mediated induction of IRS2. Genes Dev 17:1575–1580

    Article  CAS  PubMed  Google Scholar 

  31. Tuttle RL, Gill NS, Pugh W, Lee JP, Koeberlein B, Furth EE, Polonsky KS, Naji A, Birnbaum MJ (2001) Regulation of pancreatic beta-cell growth and survival by the serine/threonine protein kinase Akt1/PKBalpha. Nat Med 7:1133–1137

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by the Swedish Heart and Lung Foundation, Swedish Scientific Research Council, The Vascular Wall Program, and Lund University. David Erlinge is a holder of The Lars Werkö distinguished research fellowship from the Swedish Heart and Lung Foundation.

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Authors and Affiliations

  1. Department of Cardiology, Lund University, 22185, Lund, Sweden

    Chanyuan Tan, Siv Svensson, Björn Olde & David Erlinge

  2. Department of Clinical Sciences, Lund University, Clinical Research Centre, 20502, Malmö, Sweden

    Albert Salehi

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  1. Chanyuan Tan
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  2. Albert Salehi
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  3. Siv Svensson
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Correspondence to David Erlinge.

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Tan, C., Salehi, A., Svensson, S. et al. ADP receptor P2Y13 induce apoptosis in pancreatic β-cells. Cell. Mol. Life Sci. 67, 445–453 (2010). https://doi.org/10.1007/s00018-009-0191-3

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  • DOI: https://doi.org/10.1007/s00018-009-0191-3

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