Purines and cell death

Increasing evidence suggests that adenosine and ATP not only modulate cell growth and differentiation, but may also act as inducers of cell death. In the session 'Purines and cell death,' held during the Purines '96 Symposium and chaired by Claudio Franceschi (Modena, Italy) and Geoffrey Burnstock (London, UK) presentation and discussion of new studies on the modulation of cell death by adenosine and ATP raised novel implications for a possible role of purines in both development and in the pathophysiology of various diseases. The cloning of a new ligand-gated P2X receptor (the P2X7) was reported, and pharmacological studies have demonstrated that this is the unique P(2Z) receptor known to cause cell death by cytolysis. During the session, induction of apoptosis by ATP was reported in a murine macrophage cell line (confirming a role for ATP in inflammation and immunomodulation), in cultures of renal mesangial cells and of endothelial cells from bovine main pulmonary artery; furthermore, ATP was shown to modulate glutamate neurotoxicity in cerebellar granule cells, suggesting that apoptosis by ATP is not only restricted to cells of the immune lineage, but may represent a more general means to regulate cell survival. Adenosine and its derivatives have been known for years to induce apoptosis of human lymphoid tissues, but it has been demonstrated only recently that these effects can also occur in other cell types, and that they can be due either to the activation of extracellular adenosine receptors or to an intracellular mechanism of action. During the session 'Purines and cell death,' various authors reported apoptosis by adenosine analogues in human peripheral blood mononuclear cells, but also in chick sympathetic neurons, rat chromaffin cells, rat cerebellar granule neurons, intact chick embryos and rat microglial cells, suggesting that adenosine may play an important role not only in modulation of survival of lymphoid cells but also in the development and remodelling of the nervous system. A dual role for the adenosine A3 receptor in cell survival was also demonstrated in cells of the astroglial lineage, as shown by induction of apoptosis at high concentrations of A3 receptor-agonists and protection from spontaneous cell death at low concentrations, suggesting that this receptor may promote either cell death or survival likely depending on the metabolic and functional state of the tissue. It was also reported that, following an ischemic episode, an alterated metabolism of adenine nucleotides and nucleosides in the heart may be the basis of the lack of recovery of phosphorylated forms of adenosine due to oxidative stress, therefore contributing to heart damage. Taken together, all these data confirm the involvement of purines in modulation of cell survival in various organs and systems; moreover, based on these data, it is expected that the characterization of the specific purinoceptor subtypes involved in these actions may lead to the development of entirely new therapeutic approaches to several diseases.