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The P2X7 receptor is known as a low\u2010sensitivity P2 receptor that requires a high extracellular ATP (eATP) concentration for activation. PC increased the eATP level but was not sufficient to activate P2X7 receptors. Here, we show that astrocytes possess an elaborate mechanism for activation of P2X7 receptors, thus contributing to ischemic tolerance. Nicotinamide adenine dinucleotide (NAD\n                    <jats:sup>+<\/jats:sup>\n                    ) was shown to increase the sensitivity of P2X7 receptors to eATP via ecto\u2010ADP\u2010ribosyltransferase 2 (ARTC2)\u2010catalyzed ADP\u2010ribosylation in peripheral immune cells. Although ARTC2\u2010positive signals were mostly absent in the na\u00efve brain, they were selectively increased in astrocytes by PC. The spatiotemporal pattern of PC\u2010evoked ARTC2 was well associated with that of P2X7 receptors. In the in vitro experiments, NAD\n                    <jats:sup>+<\/jats:sup>\n                    increased the sensitivity of P2X7 receptors to ATP, and at higher concentrations, NAD\n                    <jats:sup>+<\/jats:sup>\n                    itself activated P2X7 receptors without eATP in cultured astrocytes. In the in vivo experiments using middle cerebral artery occlusion model mice, the PC\u2010evoked increase in HIF\u20101\u03b1 in astrocytes was abolished by the ARTC2 inhibitor S\u2009+\u200916a. S\u2009+\u200916a also abolished PC\u2010evoked ischemic tolerance. Taken together, the results suggested that P2X7 receptors can be sensitized to ATP by NAD\n                    <jats:sup>+<\/jats:sup>\n                    \/ARTC2\u2010catalyzed ADP\u2010ribosylation, which allows astrocytes to drive P2X7 receptor\u2010mediated ischemic tolerance even though PC only slightly increases the amount of eATP.\n                  <\/jats:p>","DOI":"10.1002\/glia.23998","type":"journal-article","created":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T17:57:54Z","timestamp":1622656674000},"page":"2100-2110","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Mechanisms underlying sensitization of P2X7 receptors in astrocytes for induction of ischemic tolerance"],"prefix":"10.1002","volume":"69","author":[{"given":"Yuri","family":"Hirayama","sequence":"first","affiliation":[{"name":"Department of Pharmacology Chiba University Graduate School of Medicine  Chiba Japan"},{"name":"Department 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