beyond its role of cellular energy currency and phosphate donor , atp plays a potent signaling role through its extracellular release and activation of cell surface purinergic receptors .
fast responses to atp are mediated through activation of p2x receptors , a family ( p2x1p2x7 ) of atp - activated ligand - gated ion channels and metabotropic effects through the activation of p2y receptors ( p2y12 , p2y4 , p2y6 , p2y1114 ) which couple to heterotrimeric g proteins . human leukocytes including monocytes , mast cells , neutrophils and central microglia express a diverse repertoire of p2y receptors though p2x1 , p2x4 and p2x7 are the dominant p2x subtypes present .
activation of purinergic receptors in leukocytes is coupled to the production and secretion of cytokines and other pro - inflammatory molecules including prostaglandin e2 .
purinergic receptors are associated with inflammation , with some receptors inhibited either directly ( p2y12 ) or indirectly through the activity of anti - thrombotic , in the case of platelet p2y12 , or anti - inflammatory agents , in the case of the action of statins on monocyte p2x4 .
atp can act as a non - peptide damage - associated molecular pattern ( damp ) release from injured cells and tissues . in this fashion
the release of cellular atp is unregulated and released due to cell lysis or puncture .
cell surface purinergic receptors are activated by this atp damp signal which serves to initiate an inflammatory response and promote wound healing .
however , atp can be released from cells physiologically and act as a critical signal for painful , inflammatory processes .
do release other nucleotides including utp and udp - sugars but our focus here is atp release . mechanisms of atp release during physiological processes remain diverse and controversial .
investigation into how cellular stress stimulates atp release in non - leukocytes suggests roles for connexin and pannexin hemichannels , maxi- and volume - regulated anion channels and efflux through the p2x7 receptor , though release routes and signal transduction mechanism underlying atp release in leukocytes remain poorly defined .
in neutrophils atp is released in response to activation of fmlp receptor by bacterially derived n - formylmethionine .
the precise release mechanism is unclear but occurs at the leading edge of migrating neutrophils .
released atp and its subsequent metabolism to adenosine at the cell surface activate p2y2 and a3 receptors serving to direct cell orientation and promote migration in response to chemotactic signals .
bacterially derived lipopolysaccharide can stimulate central microglia to secrete atp which in - turn activates neighboring astrocytes and modulates excitatory neurotransmission .
this raises the possibility that atp can act in a feed forward loop possibly amplifying responses to itself or other external cues which couple to atp secretion .
furthermore , such constitutive secretion leads to activation of cell surface gq - coupled p2y receptors which elevate intracellular calcium levels through release of calcium .
this mode of constitutive secretion generates a constant pericellular atp cloud or  halo  which appears to be important in regulating intracellular calcium homeostasis following p2y receptor activation . in cells of hematopoietic lineage such as monocyte / macrophage , nk killer and mast cells , secretory lysosomes have evolved as bifunctional organelles which combine classical degradative properties with secretion .
the mechanism of lysosomal atp transport remains undefined though a nucleotide transporter ( v - nut ) has been characterized for other atp containing vesicles .
the signal transduction coupling external cues such as cytokines , chemokines and bacterially derived molecules to atp release is poorly defined .
what are the release machines in leukocytes and do they differ from other cell types ? it is expected that therapeutic intervention in agonist stimulated atp release is a potentially novel route to pharmacological modulation of innate immune responses but also in chronic inflammatory disease where normal inflammatory responses are heighten and act deleteriously .
 release and reception of extracellular atp by leukocytes plays a critical role in immune responses to infection , injury and cardiovascular disease . 
 leukocytes of both the innate , adaptive immune and central nervous system express a repertoire of cell surface receptors for atp ( p2x and p2y receptors ) and its metabolites . 
 atp acts as a damage - associated molecule pattern ( damp ) released by injured or dying cells . 
 detection of released atp by neighboring leukocytes initiates inflammation and wound healing . 
 however , recent evidence from our group and others suggests atp release by leukocytes themselves serves to regulate homeostatic mechanisms and coordinate responses to external pro - inflammatory cues . 
 examples include the homeostatic control of intracellular calcium and regulation of migratory guidance during chemotactic response to external cues . 
 though there has been some progress in elucidating atp release mechanisms of some mammalian cells types , release conduits and coupling signal transduction machinery remain larger elusive for leukocytes . 
 our recent studies suggest a role for secretory lysosomes in releasing atp in monocytes . though poorly defined , 
 targeting atp release mechanisms in leukocytes have great anti - inflammatory potential . 
Purinergic Signaling in Blood Cells and Leukocytes
ATP Release Mechanisms in Leukocytes
Agonist Stimulated ATP Release
Lysosomes as ATP Release Machines
Future Investigation