Adenosine-induced cell death: evidence for receptor-mediated signalling

Adenosine modulates the proliferation, survival and apoptosis of many diffe rent cell types, ranging from epithelial, endothelial and smooth muscle cel ls, to cells of the immune and neural lineages. In this review, we critical ly discuss the available in vitro and in vivo data which support a role for adenosine in both development-associated apoptosis, and in diseases charac terized by either pathologically increased cell death (e.g., ischemia, trau ma and aging-associated neurodegeneration) or abnormally reduced spontaneou s apoptosis (e.g., cancer). Particular emphasis is given to the possible ro le of extracellular adenosine receptors, since these may represent novel an d attractive molecular targets for the pharmacological modulation of apopto sis. In some instances, adenosine-induced cell death has been demonstrated to require entry of the nucleoside inside cells; however, in many other cas es, activation of specific adenosine extracellular receptors has been demon strated. Of the four G protein-coupled adenosine receptors so far identifie d, the A(2A) and the A(3) receptors have been specifically implicated in mo dulation of cell death. For the A(3) receptor, results obtained by exposing both cardiomyocytes and brain astrocytes to graded concentrations of selec tive agonists suggest induction of both cell protection and cell death. Suc h opposite effects, which likely depend on the degree of receptor activatio n, may have important therapeutic implications in the pharmacological modul ation of cardiac and brain ischemia. For the A(2A) receptor, recent intrigu ing data suggest a specific role in immune cell death and immunosuppression , which may be relevant to both adenosine-deaminase-immunodeficiency syndro me (a pathology characterized by accumulation of adenosine to toxic levels) and in tumors where induction of apoptosis via activation of specific extr acellular receptors may be desirable. Finally, preliminary data suggest tha t, in a similar way to the adenosine-deaminase-immunodeficiency syndrome, t he abnormal accumulation of adenosine in degenerative muscular diseases may contribute to muscle cell death. Although the role of adenosine receptors in this effect still remains to be determined, these data suggest that aden osine-induced apoptosis may also represent a novel pathogenic pathway in mu scular dystrophies.