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Elevated hemichannel (HC) activity formed by connexins (Cxs) or pannexin1 (Panx1) largely explains brain dysfunctions commonly caused by neuroinflammation. Glia express HCs formed by Cxs 43, 30, or 26, while glia and neurons both express HCs formed by Panx1. Cx43 HCs allow for the influx of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    , which promotes glial reactivity, enabling the release of the gliotransmitters that contribute to neuronal over\u2010stimulation. Valproate (VPA), an antiseizure medication, has pleiotropic actions on neuronal molecular targets, and their action on glial cell HCs remains elusive. We used HeLa cells transfected with Cx43, Cx30, Cx26, or Panx1 to determine the effect of VPA on HC activity in the brain. VPA slightly increased HC activity under basal conditions, but significantly enhanced it in cells pre\u2010exposed to conditions that promoted HC activity. Furthermore, VPA increased ATP release through Cx43 HCs. The increased HC activity caused by VPA was resistant to washout, being consistent with in silico studies, which predicted the binding site for VPA and Cx43, as well as for Panx1 HCs on the intracellular side, suggesting that VPA first enters through HCs, after which their activity increases.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc16062-fig-0007-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.16062","type":"journal-article","created":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T00:19:34Z","timestamp":1706660374000},"page":"1045-1059","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The antiseizure medication valproate increases hemichannel activity found in brain cells, which could worsen disease outcomes"],"prefix":"10.1111","volume":"168","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7495-7695","authenticated-orcid":false,"given":"Claudia","family":"Garc\u00eda\u2010Rodr\u00edguez","sequence":"first","affiliation":[{"name":"Centro Interdisciplinario de Neurociencias de Valpara\u00edso, Instituto de Neurociencias, Universidad de Valpara\u00edso  Valpara\u00edso Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8127-7540","authenticated-orcid":false,"given":"Yorley","family":"Duarte","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias de la Vida, Center for Bioinformatics and Integrative Biology Universidad Andr\u00e9s Bello  Santiago Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8295-2133","authenticated-orcid":false,"given":"\u00c1lvaro O.","family":"Ardiles","sequence":"additional","affiliation":[{"name":"Centro Interdisciplinario de Neurociencias de Valpara\u00edso, Instituto de Neurociencias, Universidad de Valpara\u00edso  Valpara\u00edso Chile"},{"name":"Facultad de Medicina, Escuela de Medicina Universidad de Valpara\u00edso  Valpara\u00edso Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3811-0347","authenticated-orcid":false,"given":"Juan C.","family":"S\u00e1ez","sequence":"additional","affiliation":[{"name":"Centro Interdisciplinario de Neurociencias de Valpara\u00edso, Instituto de Neurociencias, Universidad de Valpara\u00edso  Valpara\u00edso Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,1,30]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2008.10.001"},{"key":"e_1_2_11_3_1","first-page":"161","article-title":"A study of serum and cerebrospinal fluid magnesium in convulsive disorders","volume":"33","author":"Afzal S.","year":"1985","journal-title":"The Journal of the Association of Physicians of India"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.reprotox.2010.09.008"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjp.2008.112"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21207510"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2017.09.004"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.1033035"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2017.00021"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1139\/bcb-2013-0051"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23031369"},{"key":"e_1_2_11_12_1","volume-title":"Epilepsy, antiepileptic drugs, and aggression: An evidence\u2010based review","author":"Brodie M. 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