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].