Extracellular ATP: A powerful inflammatory mediator in the central nervous system. (15th February 2023)

• Record Type: Journal Article
• Authors: Di Virgilio, Francesco; Vultaggio-Poma, Valentina; Falzoni, Simonetta; Giuliani, Anna Lisa
• Is Part Of: Neuropharmacology. Volume 224(2023)
• Publication Date: 2023-02-15
• Subjects: Extracellular ATP -- Neuroinflammation -- PAMP -- DAMP -- Central nervous system -- P2X7 receptor; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2022.109333
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: 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 Ca 2+, whether in the extracellular milieu or in the cytoplasm, establishing an inverse reciprocal relationship, i.e. high extracellular Ca 2+ levels are associated to negligible eATP, while low intracellular Ca 2+ 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. This article is part of the Special Issue on 'Purinergic Signaling: 50 years'. Highlights: Extracellular nucleotides are universal extracellular signaling molecules. In the brain, ATP is a danger signal and a powerful pro-inflammatory mediator. Multiple ATP receptors with varying affinity are expressed in the brain. ATP signaling is increasingly involved in brain homeostasis in health and disease. Purinergic signaling is an appealing target for the therapy of CNS diseases.