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Extracellular nucleotides, released by stressed and damaged neurons, act as danger signals to microglia through various purinergic\/pyrimidinergic receptors. In the CNS, the UDP receptor P2Y6 is mostly expressed in microglia, where its activation induces phagocytosis, a homeostatic function that is dysregulated in several neurodegenerative diseases and in chronic pain. Yet, modulatory mechanisms impacting P2Y6 activity remain to be identified. The microglial \u03b22 adrenergic receptor (ADRB2) for norepinephrine represents a promising candidate for modulation of P2Y6 receptors. Our calcium imaging data indicate that exposure to the ADRB2 agonist isoproterenol inhibits the calcium transients evoked by activation of Gq\u2010coupled P2Y6 receptors in primary mouse microglia. This functional modulation, suppressed by the selective ADRB2 antagonist ICI\u2010118551, is conserved in human iPSC\u2010derived microglia. Accordingly, we observed that the phagocytotic activity induced by P2Y6 is reduced by ADRB2 signaling in both mouse and human microglia. Finally, we report that ADRB2 activation is linked to a decrease in P2Y6 mRNA expression. These findings provide evidence that metabotropic and transcriptional crosstalks between nucleotide and adrenergic transductions control microglial responses in the CNS, potentially contributing to the pathophysiology of neuro\u2010immune disorders and chronic pain conditions.<\/jats:p>","DOI":"10.1002\/glia.70054","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T05:39:54Z","timestamp":1752730794000},"page":"2025-2034","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Adrenergic Control of <scp>P2Y6<\/scp> Receptor\u2010Dependent Phagocytosis in Rodent and Human Microglia"],"prefix":"10.1002","volume":"73","author":[{"given":"Thomas","family":"Deluc","sequence":"first","affiliation":[{"name":"Department of Neurology and Neurosurgery, Montreal Neurological Institute McGill University  Montreal Quebec Canada"},{"name":"Alan Edwards Centre for Research on Pain McGill University  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariel","family":"Ase","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery, Montreal Neurological Institute McGill University  Montreal Quebec Canada"},{"name":"Alan Edwards Centre for Research on Pain McGill University  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie\u2010France","family":"Dorion","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery, Montreal Neurological Institute McGill University  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilles","family":"Maussion","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery, Montreal Neurological Institute McGill University  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeman","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery, Montreal Neurological Institute McGill University  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita T. 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