1 Extracellular guanosine has diverse e ects on many cellular components of the central nervous system, some of which may be related to its uptake into cells and others to its ability to release adenine-based purines from cells. Yet other e ects of extracellular guanosine are compatible with an action on G-protein linked cell membrane receptors. 4 This site was speci®c for guanosine, and the order of potency in displacing 50 nM [ 3 H]-guanosine was: guanosine=6-thio-guanosine4inosine46-thio-guanine4guanine. Other naturally occurring purines, such as adenosine, hypoxanthine, xanthine ca eine, theophylline, GDP, GMP and ATP were unable to signi®cantly displace the radiolabelled guanosine. Thus, this binding site is distinct from the well-characterized receptors for adenosine and purines. 5 The addition of GTP produced a small concentration-dependent decrease in guanosine binding, suggesting this guanosine binding site was linked to a G-protein.

Like adenine-based purines, extracellular nonadenine-based purines have a multitude of trophic effects on the growth, differentiation, and survival of target cells. The nonadenine-based purines, which include guanosine, inosine, and GTP, apparently exert their trophic effects by interacting with both intercellular targets as well as those on the cell surface. Specifically, guanosine and inosine target the protein kinase N-kinase, in promoting remarkable nerve process extension, even in long tracts of the central nervous system after injury. In contrast, GTP may exert its effects via a cell surface receptor coupled to the release of calcium from internal stores. In other cases trophic effects may be mediated by the enhancement of release of adenine-based purines by guanosine. Additionally, evidence is presented for the existence of a high-affinity binding site for guanosine with receptor-like characteristics on the plasma membranes of astrocytes and brain tissue. This site may be G-protein-coupled and exert its effects through activation of the MAP kinase cascade. One effect apparently mediated through this mechanism is the production and release by astrocytes of trophic protein growth factors such as NGF and TGFβ. These have substantial neuroprotective effects. Additionally, this pathway is apparently involved in modulating the expression of P2Y 1 and P2Y 2 receptors in response to extracellular guanosine. Extracellular nonadenine-based purines can interact with other growth factors, but these interactions are not always synergistic. For example, combinations of guanosine and FGF are antagonistic and reduce the growth of microvascular cells in vitro. Some of the properties of the nonadenine-based purines likely derive from their unique intracellular metabolism in which conversion of guanine to xanthine is the final catabolic step. This step is catalyzed by guanase, the activity of which varies markedly in different brain regions, raising the possibility that guanine or guanosine are involved in neurotransmission. Together these data suggest several potentially useful pharmacological approaches involving nonadenine-based purines to modulate trophic effects in the central nervous system. Drug Dev. Res. 52:303-315, 2001.

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