Once in the extracellular space, ATP undergoes rapid stepwise dephosphorylation by ecto-nucleotidases (21, 22) including the E-NTPDase CD39, which converts ATP or ADP to ADP or AMP, respectively, and the 5′-nucleotidase CD73, which dephosphorylates AMP to adenosine (18, 23) (Figure 1). Additional enzymes whose ecto-activity contributes toward extracellular adenosine generation are other E-NTPDases, members of the ecto-phosphodiesterase/pyrophosphatase (E-NPP) family, nicotinamide adenine dinucleotide (NAD+) glycohydrolases, the prostatic acid phosphatase (PAP), and the alkaline phosphatase (ALP) (21) (Figure 1). Briefly, the co-enzyme NAD+, another key cellular component whose extracellular concentration significantly rises in injured tissue (24, 25), is converted to adenosine diphosphate ribose (ADPR) by the NAD+ glycohydrolase CD38 (26), while ADPR as well as ATP are metabolized to AMP by the E-NPP CD203a (27). Moreover, PAP, which is predominantly, but non-exclusively, expressed in prostate tissue (28), is capable of converting extracellular AMP to adenosine (29), whereas ALP catalyzes the hydrolysis of ATP, ADP and AMP to adenosine (21). Finally, adenosine can also be produced intracellularly either by S-adenosylhomocysteine hydrolase (SAHH)-exerted hydrolysis of S-Adenosylhomocysteine (SAH), a metabolite of the transmethylation pathway, or due to soluble CD73-mediated catabolism of AMP, a nucleoside participating in multiple cellular processes and whose concentration rises within cells of low energy charge (30) (Figure 1). Intracellularly-generated adenosine can be secreted in a diffusion limited-manner through bidirectional equilibrative nucleoside transporters (ENTs) (31). However, although there is evidence suggesting that hypoxia can boost intracellular adenosine production (32, 33), the contribution of this pathway toward injury-caused interstitial adenosine buildup is considered minor due to concurrent hypoxia-induced downregulation of the aforementioned transporters (34, 35). Given its diverse effects, adenosine presence at the extracellular space is subject to tight spatiotemporal control (12, 13, 36). For instance, extracellular accumulation of adenosine is counteracted by its inward transfer through ENTs or concentrative, sodium gradient-dependent, symporters (31) as well as by the function of intra/extracellular adenosine deaminase (ADA) and of cytosolic adenosine kinase (ADK), which respectively convert adenosine to inosine or AMP (37) (Figure 1).