Purinergic signaling system

Purinergic signaling is a complex extracellular communication system mediated by purine nucleotides, such as ATP and ADP, and nucleosides, such as adenosine (Burnstock, 2014). In the local microenvironment, particularly within tumors or sites of injury, extracellular ATP (eATP) acts as a potent pro-inflammatory danger signal by activating P2X and P2Y receptors on various cell types. This signal is tightly regulated by a cascade of ectonucleotidases, most notably CD39 and CD73, which sequentially hydrolyze ATP into adenosine (Antonioli et al., 2013). Adenosine then binds to P1 receptors, such as the A2A and A2B receptors, to exert strong immunosuppressive effects, helping to resolve inflammation but also allowing tumors to evade immune detection (Vijayan et al., 2017). This ATP-adenosine axis is a critical regulator of the balance between immune activation and suppression. Therapeutic strategies targeting this system include P2Y12 inhibitors for cardiovascular protection and CD73 or A2AR antagonists designed to restore anti-tumor immunity in the oncology setting (Cattaneo, 2015; Vijayan et al., 2017). The ubiquitous nature of these receptors and enzymes makes the system a versatile but challenging target for drug development due to potential pleiotropic effects.

Other names

ATP-adenosine axisPurinergic pathwayExtracellular nucleotide signalingPurinergic signaling network

The purinergic signaling system is modulated through several mechanisms: antagonism of P2Y12 receptors to prevent platelet aggregation (Cattaneo, 2015); inhibition of ectonucleotidases CD39 and CD73 to prevent the formation of immunosuppressive adenosine (Antonioli et al., 2013); and antagonism of A2A receptors to block adenosine-mediated suppression of immune cells (Vijayan et al., 2017).