A central role for ATP signaling in glial interactions in the CNS

The purine ATP has a prominent regulatory role in CNS function and pathology due to its actions on glial cells - microglia, astrocytes and oligodendrocytes. ATP serves as a ubiquitous ‘gliotransmitter’ that is released by astrocytes to activate purine receptors on neighbouring cells. In pathology, ATP release from glia and damaged cells mediates both tissue destruction and repair. The actions of ATP on glia are mediated via a wide range of receptors, broadly divided into ionotropic P2X and metabotropic (G-protein coupled receptors (GPCR) P2Y receptors, of which there are multiple subtypes (P2X1-P2X7 and P2Y1-P2Y14). ATP-mediated interactions between astrocytes and microglia are at the centre of immune responses in the CNS, with prominent roles for the P2X4, P2X7, P2Y1, P2Y6 and P2Y12 receptor subtypes. In oligodendrocytes, P2X7 and P2Y1 receptor subtypes have a bipartite cytotoxic and cytoprotective function, respectively. Notably, glial ATP signalling is dysregulated with ageing and is implicated in impaired myelination and immunity in Alzheimer’s disease. Glial purine receptors provide potential therapeutic targets in multiple neuropathologies, with prominent roles in stroke, neuroinflammation, Multiple Scelerosis, Alzheimer’s disease, neuropathic pain and traumatic injury. However, the ‘Jeckyll and Hyde’ nature of purine signalling underscores the importance of further research and a comprehensive understanding of the roles of the different purine receptors in mediating tissue damage and repair.