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Intracellular, nonreceptor-mediated signaling by adenosine

Induction and prevention of neuronal apoptosis

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Abstract

Inhibitory effect of adenosine on the isolated heart muscle and vascular system were first described in 1929 (1). Since then, numerous reviews have been published on the diverse actions of this nucleoside on a wide variety of cell types. Essentially all effects of adenosine in neurons and non-neuronal cells are mediated by activation of nucleoside membrane receptors coupled to specific intracellular second messenger pathways. This brief review describes two novel actions of adenosine in peripheral sympathetic neurons, which are not mediated by adenosine receptors. First is described how adenosine and related nucleosides are able to induce apoptosis during the initial stages of neuronal growth and development in vitro and in vivo. Second is discussed how adenosine is able to prevent or delay apoptosis in more mature sympathetic neurons subjected to nerve growth factor deprivation in culture. Both the induction and prevention of apoptosis are independent of receptor activation, and totally dependent on the intracellular accumulation and subsequent phosphorylation of adenosine. The physiological significance and mechanisms by which adenosine can induce apoptosis in one situation, and rescue from apoptosis in another, are described in this article.

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References

  1. Drury A. N. and Szent-Gyorgi A. (1929) The physiological activity of adenine compounds with special reference to their actions upon the mammalian heart. J. Physiol. 68, 213–237.

    PubMed  CAS  Google Scholar 

  2. Knudsen T. B., Gray M. K., Church J. K., Blackburn M. R., Airhart M. J., Kellems R. E., and Skalko R. G. (1989) Early postimplantation embryolethality in mice following in utero inhibition of adenosine deaminase with 2′-deoxycoformycin. Teratology 40, 615–626.

    Article  PubMed  CAS  Google Scholar 

  3. Polmar S. H., Stern R. C., Schwartz A. L., Wetzler E. M., Chase P. A., and Hirschhorn R. (1976) Enzyme replacement therapy for adenosine deaminase deficiency and severe combined immunodeficiency. N. Engl. J. Med. 295, 1337–1343.

    Article  PubMed  CAS  Google Scholar 

  4. Hirschhorn R., Paageorgiou P. S., Kesarwala H. H., and Taft L. T. (1980) Amerioration of neurologic abnormalities after “enzyme replacement” in adenosine deaminase deficiency. N. Engl. J. Med. 303, 377–380.

    Article  PubMed  CAS  Google Scholar 

  5. Wakade T. D., Palmer K. C., McCauley R., Przywara D. A., and Wakade A. R. (1995a) Adenosine-induced apoptosis in embryonic chick sympathetic neurons: a new physiological role for adenosine. J. Physiol. 488, 123–138.

    PubMed  CAS  Google Scholar 

  6. Wakade A. R., Przywara D. A., Palmer K. W., Kulkarni J. S., and Wakade T. D. (1995b) Deoxynucleoside induces neuronal apoptosis independent of neurotrophic factors. J. Biol. Chem. 270, 17,986–17,982.

    CAS  Google Scholar 

  7. Wakade A. R., Wakade T. D., Malhotra R. K., and Bhave S. V. (1988) Excess K+ and phorbol ester activate protein kinase C and support the survival of chick sympathetic neurons in culture. J. Neurochem. 51, 975–983.

    Article  PubMed  CAS  Google Scholar 

  8. Wyllie A. H. (1980) Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 284, 555–556.

    Article  PubMed  CAS  Google Scholar 

  9. Thompson C. B. (1995) Apoptosis in pathogenesis and treatmentof disease. Science 267, 1456–1462.

    Article  PubMed  CAS  Google Scholar 

  10. Zhao Z., Crossland W. J., Kulkarni J. S., Wakade T. D. and Wakade A. R. (1999) 2′-Deoxyadenosine causes cell death in chick embryo sympathetic ganglia and brain. Cell. Tissue Res. 296, 281–291.

    Article  PubMed  CAS  Google Scholar 

  11. Wakade A. R., Guo X., Palmer K. C., Kulkarni J. S., Przywara D. A., and Wakade T. D. (1996) 2′-deoxyadenosine induces apoptosis in rat chromaffin cells. J. Neurochem. 67, 2273–2281.

    Article  Google Scholar 

  12. Schwartz A. L., Stern R. C., and Polmar S. H. (1978) Demonstration of adenosine receptor on human lymphocytes in vitro and its possible role in the adenosine deaminase-deficient form of severe combined immunodeficiency. Clin. Immunol. Immunopathol. 9, 499–505.

    Article  PubMed  CAS  Google Scholar 

  13. Kizake H., Suzuki K., Takakuma T., and Ishimura Y. (1990) Adenosine receptor-mediated accumulation of cyclic AMP-induced T-lymphocyte death through internucleosomal DNA cleavage. J. Biol. Chem. 265, 5280–5284.

    Google Scholar 

  14. Szondy Z. (1994) Adenosine stimulates DNA fragmentation in human thymocytes by Ca2+-mediated mechanism. Biochem. J. 304, 877–885.

    PubMed  CAS  Google Scholar 

  15. Abbracchio M. P., Saffrey M. J., Hopker V., and Burnstock G. (1994) Modulation of astroglial cell proliferation by analogues of adenosine and ATP in primary cultures of rat striatum. Neuroscience 59, 67–76.

    Article  PubMed  CAS  Google Scholar 

  16. Yao Y., Sei Y., Abbracchio M. P., Jiang J. L., Kim Y. C., and Jacobson K. A. (1997) Adenosine A3 receptor agonists protect HL-60 and U-937 cells from apoptosis induced by A3 antagonists. Biochem. Biophys. Res. Commun. 232, 317–221.

    Article  PubMed  CAS  Google Scholar 

  17. Plamondon H., Blondeau N., Heurteaux C., Lazdunski M., (1999) Mutually protective actions of kainic acid epileptic preconditioning and sublethal global ischemia on hippocamapal neuronal death: involvement of adenosineA1 receptors and K (ATP) channels. J. Cereb. Blood Flow Metab. 12, 1296–1308.

    Article  Google Scholar 

  18. Shneyvays V., Jacobson K. A., Li A. H., Nawrath H., Zinman T., Isaac A., Shainberg A., (2000) Induction of apoptosis in rat cardiocytes by A3 adenosine receptors and its suppression by isoproterenol. Exp. Cell Res. 25, 111–126.

    Article  Google Scholar 

  19. Brambilla R., Cattabeni F., Ceruti S., Barbeieri D., Franceschi C., Kim Y. C., et al. (2000) Activation of the A3 adenosine receptor affects cell cycle progression and cell growth. Naunyn Schmiedebergs Arch. Pharmacol. 361, 225–234.

    Article  PubMed  CAS  Google Scholar 

  20. van Lubitz D. K., Ye W., McClehan J., Lin R. C. (1999) Stimulation of adenosine A3 receptors in cerebral ischemia. Natural death, recovery or both? Ann. NY Acad. Sci. 890, 93–106.

    Article  Google Scholar 

  21. Kull J. S., Fredholm B. B., and Orrenius S., (1996) P2X purinoceptor is not important in thymocyte apoptosis. Immunol. Lett. 49, 197–201.

    Google Scholar 

  22. Thampy K. G., Barnes E. M., Jr. (1983) Adenosine transport by primary cultures of neurons from chick embryo brain. J. Neurochem 40, 874–879.

    Article  PubMed  CAS  Google Scholar 

  23. Kulkarni J. S., Wakade A. R. (1996) Quantitative analysis of similarities and differences in neurotoxicities caused by adenosine and 2′-deoxyadenosine in sympathetic neurons. J. Neurochem. 67, 778–778.

    Article  Google Scholar 

  24. Przywara D. A., Bhave S. V., Chowdhury P. S., Wakade T. D., Wakade A. R. (1993) Sites of transmitter release and relation to intracellular Ca2+ in cultured sympathetic neurons. Neuroscience 52, 973–986.

    Article  PubMed  CAS  Google Scholar 

  25. Mitchell B. S., Mejias E., Daddona P. E. and Kelly W. N. (1978) Purinergic immunodeficiency diseases. Selective toxicity of deoxyribonucleosides for T cells. Proc. Nat. Acad. Sci. USA 75, 5011–5016.

    Article  PubMed  CAS  Google Scholar 

  26. Ceruti S., Barbieri D., Veronese E., Cattabeni F., Cosarizza A., Malorni W., Franceschi C., Abbracchio M. P. (1997) Different pathways of apoptosis revealed by 2-chloroadenosine and deoxy-D-ribose in mammalian astroglial cells. J. Neurosci Res. 47, 372–383.

    Article  PubMed  CAS  Google Scholar 

  27. Ceruti S., Franceschi C., Barbeieri D., Malorni W., Camurri A., Giammarioli A. M., et al. (2000) Apoptosis induced by 2-chloro-adenosine and 2-chloro-2′deoxy-adenosinein a human astrocytoma cell line: differential mechanism and possible clinical relevance. J. Neurosci. Res. 60, 388–400.

    Article  PubMed  CAS  Google Scholar 

  28. Barbieri D., Abbracchio M. P., Salvioli S., Monti D., Cossarizza A., Ceruti S., Brambilla R., and Cattabeni F. (1998) Apoptosis by 2-chloro-2′-deoxy adenosine and 2-chloro-adenosine in human peripheral blood mononuclear cells. Neurochem Int. 32, 493–504.

    Article  PubMed  CAS  Google Scholar 

  29. Miller R. L., Adamczyk D. L., Miller W. H., Koszalka G. W., Rideout J. L., Beachman L. M., et al. (1979) Adenosine kinase from rabbit liver. II substrate and inhibitor specificity. J. Biol. Chem. 254, 2346–2352.

    PubMed  CAS  Google Scholar 

  30. Newby A. C. (1981) The interaction of inhibitors with adenosine metabolizing enzymes in intact isolated cells. Biochem. Pharmacol. 30, 2611–2615.

    Article  PubMed  CAS  Google Scholar 

  31. Andres C. M. and Fox I. H. (1979) Purification and properties of human placental adenosine kinase. J. Biol. Chem. 254, 11,388–11,393.

    CAS  Google Scholar 

  32. Mlejnek P. and Kuglik P. (2000) Induction of apoptosis in HL-60 cells by N 96)-benzyladenosine. J. Cell Biochem. 77, 6–17.

    Article  PubMed  CAS  Google Scholar 

  33. Davis P. K. and Johnson G. V. (1999) Energy metabolism and protein phosphorylation during apoptosis: a phosphorylation study of tau and high-molecular-weight tau in different PC 12 cell. Biochem. J. 15, 51–58.

    Article  Google Scholar 

  34. Wakade A. R., Kulkarni J. S., and Fujii J. T. (1998) 2′-Deoxyadenosine selectively kills non-neuronal cells without affecting survival and growth of chick dorsal root ganglion neurons. Brain Res. 788, 69–79.

    Article  PubMed  CAS  Google Scholar 

  35. Kulkarni J. S., Przywara D. A., Wakade T. D., and Wakade A. R. (1998) Adenosine induces apoptosis by inhibiting mRNA and protein synthesis in chick embryonic sympathetic neurons. Neruroscience Lett. 248, 167–190.

    Article  Google Scholar 

  36. Planet G. and Fox I. H. (1976) Inhibition of phosphorybosilpyrophosphate synthesis by purine nucleosides in human erythrocytes. J. Biol. Chem. 251, 5839–5844.

    PubMed  CAS  Google Scholar 

  37. Tinton S. A., Chow S. C., Buc-Calderon P., Kass G. E., and Orrenius S. (1995) Adenosine inhibits protein synthesis in isolated rat hepatocytes. Evidence for a lack of involvement of extracellular calcium in the mechanism of inhibition. Eur. J. Biochem. 229, 419–425.

    Article  PubMed  CAS  Google Scholar 

  38. Tinton S. A., Buc-Calderon P. (1995) Homocysteine enhances the inhibitory effect of extracellular adenosine on the synthesis of proteins in isolated rat hepatocytes. Biochem. J. 310, 893–896.

    PubMed  CAS  Google Scholar 

  39. Harrington E. O., Smeglin A., Parks N., Newton J., Rounds S. (2000) Adenosine induces endothelial apoptosis by activating protein tyrosine phosphatase: a possible role of p38alpha. Am. J. Physiol. Lung Cell Mol. Physiol. 279, L733–742.

    PubMed  CAS  Google Scholar 

  40. Liang P. and Pardee A. B. (1992) Differential display of eukaryotic messenger RNA by means of the polymerase chain reaction. Science 257, 967–971.

    Article  PubMed  CAS  Google Scholar 

  41. Deckwerth T. L. and Johnson E. M., Jr. (1993) Temporal analysis of events associated with programmed cell death (apoptosis) of sympathetic neurons deprived of nerve growth factor. J. Cell. Biol. 123, 1207–1222.

    Article  PubMed  CAS  Google Scholar 

  42. Deshmukh M. and Johnson E. M., Jr. (1997) Programmed cell death in neurons: Focus on the pathway of nerve growth factor deprivation-induced death of sympathetic neurons. Mol. Pharmacol. 51, 897–906.

    PubMed  CAS  Google Scholar 

  43. Przywara D. A., Kulkarni J. S., Wakade T. D., Leontiev D. V., and Wakade A. R. (1998) Pituitary adenylyl cyclase-activating polypeptide and nerve growth factor use the proteasome to rescue nerve growth factor-deprived sympathetic neurons cultured from chick embryos. J. Neurochem. 71, 1889–1897.

    Article  PubMed  CAS  Google Scholar 

  44. Matsuoka Y., Okazaki M., Takata K., Kitamura Y., Ohta S., Sekino Y., and Taniguchi T. (1999) Endogenous adenosine protects CA1 neurons from kianic acid-induced neuronal loss in the rat hippocampus. Eur. J. Neurosci. 11, 3617–3625.

    Article  PubMed  CAS  Google Scholar 

  45. Michel P. P., Marien M., Ruberg M., Colpaert F., and Agid Y. (1999) Adenosine prevents the death of mesencephalic dopaminergic neurons by a mechanism thatinvolves astrocytes. J. Neurochem. 72, 2074–2082.

    Article  PubMed  CAS  Google Scholar 

  46. Vitolo O. V., Ciotti M. T., Galli C., Borsello T., and Calissano P. (1998) Adenosine and ADP prevent apoptosis in cultured rat cerebellar granule cells. Brain Res. 809, 297–301.

    Article  PubMed  CAS  Google Scholar 

  47. Fishman P., Bar-Yehuda S., Ohana G., Pathak S., Wasserman L., Barer F., and Multani A. S. (2000) Adenosine acts as an inhibitor of lymphoma cell growth: a major role for the A3 adenosine receptors. Eur. J. Cancer 36, 1452–1458.

    Article  PubMed  CAS  Google Scholar 

  48. Stefanis L., Park D. S., Yan I., Farinelli S. E., Troy C. M., Shelanski M. L., and Greene L. A. (1996) Induction of CPP32-like activity in PC12 cells by withdrawal of trophic support. J. Biol. Chem. 271, 30,663–30,671.

    Google Scholar 

  49. Armstrong R. C., Aja T. J., Hoang K. D., Guar S., Bai X., Alnemri E. S., et al. (1997) Activation of the CED3/ICE-related protease CPP32 in cerebellar granule neurons undergoing apoptosis but not necrosis. J. Neurosci. 17, 553–562.

    PubMed  CAS  Google Scholar 

  50. Eldadah B. A., Yakovelev A. G., and Faden A. I. (1997) The role of CED-3-related cysteine proteases in apoptosis of cerebellar granule cells. J. Neurosci. 17, 6105–6113.

    PubMed  CAS  Google Scholar 

  51. Hoppe J., Schafer R., Hoppe V., and Sachinidis A. (1999) ATP and adenosine prevent via different pathways the activation of caspases in apoptotic AKR-2B fibroblasts. Cell Death Diff. 6, 546–556.

    Article  CAS  Google Scholar 

  52. Liu X., Zou H., Slaughter C., and Wang X. (1997) DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. Cell 89, 175–184.

    Article  PubMed  CAS  Google Scholar 

  53. Rydel R. E. and Greene L. A. (1998) cAMP analogs promote survival and neurite outgrowth in cultures of rat sympathetic and sensory neurons independently of nerve growth factor. Proc. Natl. Acad. Sci. USA 85, 1257–1261.

    Article  Google Scholar 

  54. Edwards S. N., Buckmaster A. E., and Tolkovsky A. M. (1991) The death programme in cultured sympathetic neurones can be suppressed at the posttranslational level by nerve growth factor, cyclic AMP, and depolarization. J. Neurochem. 57, 2140–2143.

    Article  PubMed  CAS  Google Scholar 

  55. Martin D. P., Ito A., Horigome K., Lanpe P. A., and Johnson E. M., Jr. (1992) Biochemical characterization of programmed cell death in NGF-deprived sympathetic neurons. J. Neurobiol. 23, 1205–1220.

    Article  PubMed  CAS  Google Scholar 

  56. Villalba M., Bockaert J., and Journot L. (1997) Pituitary adenylate cyclase-activating polypeptide (PACAP-38) protects cerebellar granule neurons from apoptosis by activating the mitogen-activated protein kinase (MAP kinase) pathway. J. Neurosci. 17, 83–90.

    PubMed  CAS  Google Scholar 

  57. Campard P. K., Crochemore C., Rene R., Monnier D., Koch B., and Loeffler J. P. (1997) PACAP type I receptor activation promotes cerebellar neuron survival through the cAMP/PKA signaling pathway. DNA Cell Biol. 16, 323–333.

    Article  CAS  Google Scholar 

  58. Martin D. P., Schmidt R. E., DiStefano P. S., Lowry O. H., Carter J. G., and Johnson E. M., Jr. (1998) Inhibitors of protein synthesis and RNA synthesis prevent neuronal death caused by nerve growth factor deprivation. J. Cell Biol. 106, 829–844.

    Article  Google Scholar 

  59. Cavallaro S., Copani A., D’Agata V., Musco S., Petralia S., and Ventra C., et al. (1996) Pituitary adenylate cyclase activating polypeptide prevents apoptosis in cultured cerebellar granule neurons. Mol. Pharmacol. 50, 60–66.

    Google Scholar 

  60. Phillis J. W. and O’Regan M. (1993) Prevention of ischemic brain injury by adenosine receptor activation. Drug Dev. Res. 28, 390–394.

    Article  CAS  Google Scholar 

  61. Olah M. E. and Stiles G. I. (1995) Adenosine receptor subtypes: characterization and therapeutic regulation. Ann. Rev. Pharmacol. Toxicol. 35, 581–606.

    Article  CAS  Google Scholar 

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Wakade, A.R., Przywara, D.A. & Wakade, T.D. Intracellular, nonreceptor-mediated signaling by adenosine. Mol Neurobiol 23, 137–153 (2001). https://doi.org/10.1385/MN:23:2-3:137

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