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Nonphosphorylatable Src Ser75 Mutation Increases Ethanol Preference and Consumption in Mice.

Goro Kato1

  • 1Department of Biochemistry, Faculty of Medicine, Graduate Faculty of Interdisciplinary Research, University of Yamanashi, Yamanashi 409-3898, Japan.

Eneuro
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Summary

Src phosphorylation at Ser75 influences alcohol consumption. Nonphosphorylatable Src mutants increased ethanol preference, suggesting Src

Keywords:
Srcethanol drinking behaviorknock-in micephosphorylationunique domain

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Src is a kinase highly expressed in CNS neurons, involved in development and brain functions, including alcohol consumption.
  • Src knockout mice show developmental defects, limiting behavioral studies in adults.
  • Src's unique domain phosphorylation at Ser75 by Cdk1/Cdk5 affects neuronal function.

Purpose of the Study:

  • To investigate the role of Src phosphorylation at Ser75 in regulating voluntary ethanol consumption.
  • To examine how nonphosphorylatable (Ser75Ala) and phosphomimetic (Ser75Asp) Src mutants affect ethanol intake and related behaviors.

Main Methods:

  • Generation and analysis of mice harboring Ser75Ala or Ser75Asp Src mutants.
  • Measurement of ethanol preference and consumption.
  • Assessment of plasma ethanol concentrations and sedative effects.
  • Analysis of Rho-associated kinase (ROCK) activity and Akt phosphorylation in the striatum.

Main Results:

  • Mice with the Ser75Ala Src mutant showed significantly higher preference and consumption of ethanol solutions compared to wild-type mice.
  • No differences in plasma ethanol levels or sedative sensitivity were observed between groups.
  • The Ser75Ala mutant mice exhibited lower striatal ROCK activity and higher Akt Ser473 phosphorylation.

Conclusions:

  • Src regulates voluntary ethanol drinking in a manner dependent on Ser75 phosphorylation.
  • Specific phosphorylation of Src at Ser75 is critical for modulating alcohol consumption behaviors.
  • Altered ROCK activity and Akt phosphorylation in the striatum may underlie the observed changes in ethanol intake.