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Extracellular ATP, the levels of which significantly change during epileptic seizures, activates specific receptors leading to an increase of intracellular free Ca<jats:sup>2+<\/jats:sup>concentration ([Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>). Here, we aimed to functionally characterize human microglia obtained from cortices of subjects with temporal lobe epilepsy, focusing on the Ca<jats:sup>2+<\/jats:sup>-mediated response triggered by purinergic signaling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Fura-2 based fluorescence microscopy was used to measure [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>in primary cultures of human microglial cells obtained from surgical specimens. The perforated patch-clamp technique, which preserves the cytoplasmic milieu, was used to measure ATP-evoked Ca<jats:sup>2+<\/jats:sup>-dependent whole-cell currents.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In human microglia extracellular ATP evoked [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>increases depend on Ca<jats:sup>2+<\/jats:sup>entry from the extracellular space and on Ca<jats:sup>2+<\/jats:sup>mobilization from intracellular compartments. Extracellular ATP also induced a transient fivefold potentiation of the total transmembrane current, which was completely abolished when [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>increases were prevented by removing external Ca<jats:sup>2+<\/jats:sup>and using an intracellular Ca<jats:sup>2+<\/jats:sup>chelator. TRAM-34, a selective K<jats:sub>Ca<\/jats:sub>3.1 blocker, significantly reduced the ATP-induced current potentiation but did not abolish it. The removal of external Cl<jats:sup>\u2212<\/jats:sup>in the presence of TRAM-34 further lowered the ATP-evoked effect. A direct comparison between the ATP-evoked mean current potentiation and mean Ca<jats:sup>2+<\/jats:sup>transient amplitude revealed a linear correlation. Treatment of microglial cells with LPS for 48\u2009h did not prevent the ATP-induced Ca<jats:sup>2+<\/jats:sup>mobilization but completely abolished the ATP-mediated current potentiation. The absence of the Ca<jats:sup>2+<\/jats:sup>-evoked K<jats:sup>+<\/jats:sup>current led to a less sustained ATP-evoked Ca<jats:sup>2+<\/jats:sup>entry, as shown by the faster Ca<jats:sup>2+<\/jats:sup>transient kinetics observed in LPS-treated microglia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our study confirms a functional role for K<jats:sub>Ca<\/jats:sub>3.1 channels in human microglia, linking ATP-evoked Ca<jats:sup>2+<\/jats:sup>transients to changes in membrane conductance, with an inflammation-dependent mechanism, and suggests that during brain inflammation the K<jats:sub>Ca<\/jats:sub>3.1-mediated microglial response to purinergic signaling may be reduced.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s12974-021-02096-0","type":"journal-article","created":{"date-parts":[[2021,2,17]],"date-time":"2021-02-17T14:05:32Z","timestamp":1613570732000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["ATP-evoked intracellular Ca2+ transients shape the ionic permeability of human microglia from epileptic temporal cortex"],"prefix":"10.1186","volume":"18","author":[{"given":"Nicole Piera","family":"Palomba","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0423-5689","authenticated-orcid":false,"given":"Katiuscia","family":"Martinello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Germana","family":"Cocozza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Casciato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Addolorata","family":"Mascia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giancarlo","family":"Di Gennaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Morace","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Esposito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heike","family":"Wulff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Limatola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Fucile","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,2,15]]},"reference":[{"key":"2096_CR1","doi-asserted-by":"crossref","unstructured":"Hiragi, T., Y. 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