ATP and ADO signaling
Extracellular ATP (eATP) plays an important role in regulating inflammation and immune responses; it is rapidly released through exocytosis during stress, cell injury, and death[1]. The effects of eATP are mediated by P2 cell-surface receptors (P2R), which include trans-cell membrane cationic channels (P2XR) and G-protein coupled receptors (P2YR)[2, 3]. There are 7 P2XR and 8 P2YR, which are expressed in almost all mammalian cells [4]. In addition to its metabolic functions, eATP is an important extracellular signal molecule that triggers and regulates a variety of inflammation-related processes. ATP is involved in the chemotaxis of inflammatory cells [5, 6], production of oxygen free radicals by neutrophils [7] and production of cytokines by inflammatory cells [8]. CD39 is an enzyme that hydrolyzes eATP into adenosine monophosphate (AMP), and AMP is further converted by CD73 into nucleoside adenosine (ADO). Although the production of AMP is thought to be mainly mediated by CD39, AMP is also obtained through the transformation of NAD+ by CD38 and CD203a [9-12]. The accumulated extracellular ADO performs its regulatory functions by binding to one of four ADO receptors: A1R, A2AR, A2BR, and A3R [13, 14]. All four subtypes are members of the GPCR superfamily, and each subtype has a unique pharmacological profile, tissue distribution, and effector coupling [15]. Upon activation, Gi-coupled A1R and A3R inhibit adenylate cyclase and cyclic AMP (cAMP) production [16]while Gs-coupled A2AR and A2BR stimulate cAMP synthesis and its downstream signaling pathways[17, 18]. As a consequence, activation of A2AR and A2BR in immune cells induces strong immunosuppressive effects [19]. Finally, ADO is either removed from the extracellular space by ADO deaminase, which converts it into inosine, or is taken by nucleoside transporters back into the cell and converted back into AMP by ADO kinases[20]. CD39 is the rate-limiting enzyme in the ATP/ADP-ADO pathway. The expression of CD39 is regulated by pro-inflammatory cytokines, such as transforming growth factor-β (TGF-β), interferons (IFNs), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and prostaglandin E2 [21, 22], and processes, such as oxidative stress production and hypoxia[23, 24].