Figure 2.

Extracellular adenosine signaling and its termination. Adenosine partakes in a number of signaling events during inflammatory conditions. ATP and ADP that is released serve as the source of extracellular adenosine. CD39 (Ecto-nucleotide triphosphate diphosphohydrolase 1, E-NTPDase1) dephosphorylates extracellular ATP and ADP on the cell surface to generate AMP, which is further dephosphorylated by CD73 (ecto-5'-nucleotidase, Ecto5'NTase) into adenosine. Once generated by enzymatic dephosphorylation, adenosine plays several important roles in regulating inflammation and immunity. Binding with A2AAR and A2BAR on immune cells promotes the inhibition of inflammation mediated by a number of innate immune cells including dendritic cells, monocytes, macrophages, and neutrophils. Adenosine interaction with A2AAR on T cells has demonstrated the suppression of effector functions and promotes the transition to T-regulatory status. On vascular endothelial cells, A2AAR and A2BAR activation decreases cellular inflammatory responses and promotes the integrity of barrier functions, respectively. Epithelial cells from several tissues including lung, gastrointestinal, myocardial, and renal contain A2BAR that, when activated by adenosine, are shown to play critical roles in decreasing inflammation and promoting barrier integrity during inflammation and injury. Several mechanisms are involved in regulating adenosine in order to allow for appropriate termination of signaling. Equilibrative nucleoside transporters (ENT)-1 and−2 deplete the extracellular accumulation of adenosine by transporting it into the nucleus. Adenosine kinase and adenosine deaminase are enzymes that both act to “inactivate” adenosine and inhibit its ability to bind to its receptors. Adenosine deaminase converts adenosine back to AMP and adenosine deaminase converts adenosine to inosine, which is an important step in the metabolism of nucleotides. Components of the figure were modified from SMART Servier Medical Art Library.