Extracellular ATP: A powerful inflammatory mediator in the central nervous system

Nucleotides play a crucial role in extracellular signaling across species boundaries. All the three kingdoms of life (Bacteria, Archea and Eukariota) are responsive to extracellular ATP (eATP) and many release this and other nucleotides. Thus, eATP fulfills different functions, many related to danger-sensing or avoidance reactions. Basically all living organisms have evolved sensors for eATP and other nucleotides with very different affinity and selectivity, thus conferring a remarkable plasticity to this signaling system. Likewise, different intracellular transduction systems were associated during evolution to different receptors for eATP. In mammalian evolution, control of intracellular ATP (iATP) and eATP homeostasis has been closely intertwined with that of Ca2+, whether in the extracellular milieu or in the cytoplasm, establishing an inverse reciprocal relationship, i.e. high extracellular Ca2+ levels are associated to negligible eATP, while low intracellular Ca2+ levels are associated to high eATP concentrations. This inverse relationship is crucial for the messenger functions of both molecules. Extracellular ATP is sensed by specific plasma membrane receptors of widely different affinity named P2 receptors (P2Rs) of which 17 subtypes are known. This confers a remarkable plasticity to P2R signaling. The central nervous system (CNS) is a privileged site for purinergic signaling as all brain cell types express P2Rs. Accruing evidence suggests that eATP, in addition to participating in synaptic transmission, also plays a crucial homeostatic role by fine tuning microglia, astroglia and oligodendroglia responses. Drugs modulating the eATP concentration in the CNS are likely to be the new frontier in the therapy of neuroinflammation.

Automated summary

Nucleotides, especially extracellular ATP (eATP), play a crucial role in inter-species extracellular signaling. Different organisms have evolved sensors with varying affinity and selectivity for eATP, resulting in a highly flexible signaling system. In mammalian evolution, the control of intracellular ATP and eATP homeostasis is closely linked to that of Ca2+. Specific plasma membrane receptors, known as P2 receptors (P2Rs), sense eATP with various degrees of affinity and selectivity, adding to the plasticity of the system. The central nervous system (CNS) is a privileged site for purinergic signaling, with all brain cell types expressing P2Rs. Evidence suggests that eATP not only participates in synaptic transmission but also plays a crucial homeostatic role in brain cell responses. Modulating eATP concentration in the CNS may hold promise for the treatment of neuroinflammation.