Fig. 1.

Purinergic signaling pathways: modulation of extracellular adenosine clearance by extracellular guanosine. The pathways for release, extracellular metabolism, and downstream receptor-mediated signaling of ATP and its purine metabolites are indicated. ATP can be serially hydrolyzed to ADP and then AMP via the CD39-family nucleoside triphosphate diphosphohydrolases (NTPDs). Alternatively, ATP can be directly metabolized to AMP via ecto-nucleotide pyrophosphatases/phosphodiesterases (ENPPs). AMP hydrolysis by either the CD73 ecto-5'-nucleotidases or ecto-alkaline phosphatases (APs) generates extracellular adenosine. It is important to note that extracellular GTP, GDP, and GMP are also substrates for these various ecto-nucleotidases. Extracellular adenosine (or guanosine) can be directly released from metabolically stressed cells via efflux through equilibrative nucleoside transporters (ENTs). ENTs can also function as reuptake pathways for adenosine, guanosine, and the pyrimidine nucleosides. Alternatively, these nucleosides can be actively accumulated via the concentrative nucleoside transporters (CNTs) that function as Na⁺/nucleoside cotransporters. In some tissues, extracellular adenosine is readily converted to inosine via extracellular versions of the adenosine deaminase enzymes. Accumulation of extracellular guanosine acts to sustain higher extracellular levels of adenosine by competition for these or other mechanisms for adenosine clearance. Thus, guanosine may potentiate protective purinergic receptor signaling via adenosine receptors despite its lack of direct agonistic on these receptors. GPCR, G protein-coupled receptor.