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We recently identified brain\u2010specific serine\/threonine\u2010protein kinase 1 (BRSK1) as a substrate of PKC\u03b5. Here, we test the hypothesis that BRSK1 mediates responses to ethanol and anxiety\u2010like behaviours that are also PKC\u03b5 dependent. We used in vitro kinase assays to further validate BRSK1 as a substrate of PKC\u03b5 and used <jats:italic>Brsk1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice to assess the role of BRSK1 in ethanol\u2010 and anxiety\u2010related behaviours and in physiological responses to ethanol. We found that BRSK1 is phosphorylated by PKC\u03b5 at a residue identified in a chemical genetic screen of PKC\u03b5 substrates in mouse brain. Like <jats:italic>Prkce<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice, male and female <jats:italic>Brsk1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice were more sensitive than wild\u2010type to the acute sedative\u2010hypnotic effect of alcohol. Unlike <jats:italic>Prkce<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice, <jats:italic>Brsk1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice responded like wild\u2010type to ataxic doses of ethanol. Although in <jats:italic>Prkce<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice ethanol consumption and reward are reduced in both sexes, they were reduced only in female <jats:italic>Brsk1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice. Ex vivo slice electrophysiology revealed that ethanol\u2010induced facilitation of GABA release in the central amygdala was absent in male <jats:italic>Brsk1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice similar to findings in male <jats:italic>Prkce<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice. Collectively, these results indicate that BRSK1 is a target of PKC\u03b5 that mediates some PKC\u03b5\u2010dependent responses to ethanol in a sex\u2010specific manner and plays a role distinct from PKC\u03b5 in anxiety\u2010like behaviour.<\/jats:p>","DOI":"10.1111\/adb.13388","type":"journal-article","created":{"date-parts":[[2024,3,18]],"date-time":"2024-03-18T09:28:48Z","timestamp":1710754128000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Brain\u2010specific serine\/threonine\u2010protein kinase 1 is a substrate of protein kinase C epsilon involved in sex\u2010specific ethanol and anxiety phenotypes"],"prefix":"10.1111","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9796-2502","authenticated-orcid":false,"given":"Michael P.","family":"Dugan","sequence":"first","affiliation":[{"name":"Waggoner Center for Alcohol and Addiction Research Department of Neuroscience The University of Texas at 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