{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T02:47:02Z","timestamp":1784861222754,"version":"3.55.0"},"reference-count":52,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T00:00:00Z","timestamp":1750032000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100010446","name":"Institute for Basic Science","doi-asserted-by":"publisher","award":["IBS\u2010R001\u2010D2"],"award-info":[{"award-number":["IBS\u2010R001\u2010D2"]}],"id":[{"id":"10.13039\/501100010446","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Glia"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Trifluoperazine (TFP), a known inhibitor of Ca<jats:sup>2+<\/jats:sup>\u2010bound calmodulin (Ca<jats:sup>2+<\/jats:sup>\/CaM), has been reported to elevate cytosolic Ca<jats:sup>2+<\/jats:sup> levels by disinhibiting inositol 1,4,5\u2010triphosphate receptor 2 (IP<jats:sub>3<\/jats:sub>R2), thereby suppressing glioblastoma invasion and inducing apoptosis. Interestingly, TFP induces a sustained Ca<jats:sup>2+<\/jats:sup> plateau, sensitive to extracellular Ca<jats:sup>2+<\/jats:sup>, suggesting involvement of Ca<jats:sup>2+<\/jats:sup> entry such as store\u2010operated calcium entry (SOCE). However, the underlying molecular mechanism remains elusive. Here, we report that TFP induces sustained Ca<jats:sup>2+<\/jats:sup> signals by blocking the Ca<jats:sup>2+<\/jats:sup>\/CaM\u2010dependent desensitization of SOCE channels in cortical astrocyte cultures. TFP induces a prolonged Ca<jats:sup>2+<\/jats:sup> response, with distinct kinetics compared to other Ca<jats:sup>2+<\/jats:sup> modulators such as TFLLR\u2010NH<jats:sub>2<\/jats:sub> (a G<jats:sub>\u03b1q<\/jats:sub>\u2010coupled GPCR agonist) and thapsigargin (a sacro\/endoplasmic reticulum Ca<jats:sup>2+<\/jats:sup>\u2010ATPase inhibitor). Under extracellular Ca<jats:sup>2+<\/jats:sup>\u2010free conditions, Ca<jats:sup>2+<\/jats:sup> levels increase without reaching a plateau, suggesting that the sustained Ca<jats:sup>2+<\/jats:sup> signal relies on Ca<jats:sup>2+<\/jats:sup> influx. Pharmacological analysis shows that sustained Ca<jats:sup>2+<\/jats:sup> signals by TFP are CaM\u2010dependent. Gene silencing targeting STIM1 and Orai1\u20133 confirmed their essential roles in the sustained response. We find that TFP effectively \u201clocks open\u201d SOCE channels by inhibiting their desensitization, maintaining SOCE activity. This effect is also observed in ex\u00a0vivo hippocampal dentate gyrus astrocytes. Structural modeling supports a mechanism in which TFP disrupts the interaction between Ca<jats:sup>2+<\/jats:sup>\/CaM and the SOAR domain of STIM1. Together, these findings indicate that TFP elevates cytosolic Ca<jats:sup>2+<\/jats:sup> levels by maintaining SOCE activation, offering novel insights into the molecular actions of this drug. TFP can be a pharmacological tool for SOCE research as it locks SOCE channels open.<\/jats:p>","DOI":"10.1002\/glia.70052","type":"journal-article","created":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T06:46:33Z","timestamp":1750056393000},"page":"1989-2002","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Trifluoperazine Elevates Intracellular Ca<sup>2+<\/sup> Levels and Locks Open the Store\u2010Operated Calcium Entry Channels in Astrocytes"],"prefix":"10.1002","volume":"73","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4690-303X","authenticated-orcid":false,"given":"Jiwoon","family":"Lim","sequence":"first","affiliation":[{"name":"Cognitive Glioscience Group, Center for Cognition and Sociality Institute for Basic Science (IBS)  Daejeon Republic of Korea"},{"name":"IBS School University of Science and Technology (UST)  Daejeon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wongu","family":"Youn","sequence":"additional","affiliation":[{"name":"Cognitive Glioscience Group, Center for Cognition and Sociality Institute for Basic Science (IBS)  Daejeon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3555-0980","authenticated-orcid":false,"given":"C. 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