Brain-specific serine/threonine-protein kinase 1 is a substrate of protein kinase C epsilon involved in sex-specific ethanol and anxiety phenotypes.

Autor: Dugan MP; Waggoner Center for Alcohol and Addiction Research, Department of Neuroscience, The University of Texas at Austin, Austin, Texas, USA., Maiya R; Waggoner Center for Alcohol and Addiction Research, Department of Neuroscience, The University of Texas at Austin, Austin, Texas, USA.; Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA., Fleischer C; Waggoner Center for Alcohol and Addiction Research, Department of Neuroscience, The University of Texas at Austin, Austin, Texas, USA., Bajo M; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA., Snyder AE; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA., Koduri A; Waggoner Center for Alcohol and Addiction Research, Department of Neuroscience, The University of Texas at Austin, Austin, Texas, USA., Srinivasan S; Waggoner Center for Alcohol and Addiction Research, Department of Neuroscience, The University of Texas at Austin, Austin, Texas, USA., Roberto M; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA., Messing RO; Waggoner Center for Alcohol and Addiction Research, Department of Neuroscience, The University of Texas at Austin, Austin, Texas, USA.
Jazyk: angličtina
Zdroj: Addiction biology [Addict Biol] 2024 Mar; Vol. 29 (3), pp. e13388.
DOI: 10.1111/adb.13388
Abstrakt: Protein kinase C epsilon (PKCε) regulates behavioural responses to ethanol and plays a role in anxiety-like behaviour, but knowledge is limited on downstream substrates of PKCε that contribute to these behaviours. We recently identified brain-specific serine/threonine-protein kinase 1 (BRSK1) as a substrate of PKCε. Here, we test the hypothesis that BRSK1 mediates responses to ethanol and anxiety-like behaviours that are also PKCε dependent. We used in vitro kinase assays to further validate BRSK1 as a substrate of PKCε and used Brsk1 -/- mice to assess the role of BRSK1 in ethanol- and anxiety-related behaviours and in physiological responses to ethanol. We found that BRSK1 is phosphorylated by PKCε at a residue identified in a chemical genetic screen of PKCε substrates in mouse brain. Like Prkce -/- mice, male and female Brsk1 -/- mice were more sensitive than wild-type to the acute sedative-hypnotic effect of alcohol. Unlike Prkce -/- mice, Brsk1 -/- mice responded like wild-type to ataxic doses of ethanol. Although in Prkce -/- mice ethanol consumption and reward are reduced in both sexes, they were reduced only in female Brsk1 -/- mice. Ex vivo slice electrophysiology revealed that ethanol-induced facilitation of GABA release in the central amygdala was absent in male Brsk1 -/- mice similar to findings in male Prkce -/- mice. Collectively, these results indicate that BRSK1 is a target of PKCε that mediates some PKCε-dependent responses to ethanol in a sex-specific manner and plays a role distinct from PKCε in anxiety-like behaviour.
(© 2024 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)
Databáze: MEDLINE
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