Leucine induces phosphorylation and activation of p70S6K in cortical neurons via the system L amino acid transporter

J Neurochem. 2008 Jul;106(2):934-42. doi: 10.1111/j.1471-4159.2008.05438.x. Epub 2008 Apr 24.


p70S6 kinase is a multipotent kinase that phosphorylates substrates in response to extracellular stimuli. This kinase activity inhibits apoptosis, regulates cell size and controls translation. In the CNS, p70S6K also participates in synaptic plasticity. In this study, we report that leucine, a branched-chain amino acid, induces phosphorylation and activation of p70S6 kinase in cortical neurons. Leucine also induces phosphorylation of S6 protein, a substrate of p70S6K. These effects of leucine are completely inhibited by rapamycin, consistent with mammalian target of rapamycin mediating p70S6 phosphorylation. Finally, we demonstrate that the action of leucine on cortical neurons is mediated by the system L amino acid transporter. Neurons express components of system L amino acid transporter LAT1, LAT2, and CD98. Leucine uptake and its effect on p70S6 kinase are both inhibited by a specific inhibitor of system L amino acid transporter. We propose that leucine plays important roles in regulating signaling by p70S6 kinase by acting as an intercellular communicator in the CNS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport Systems / genetics
  • Amino Acid Transport Systems / physiology*
  • Amino Acids, Branched-Chain / pharmacology
  • Animals
  • Cells, Cultured
  • Cerebral Cortex / cytology*
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Embryo, Mammalian
  • Gene Expression Regulation / drug effects
  • Immunosuppressive Agents / pharmacology
  • Leucine / drug effects*
  • Leucine / metabolism
  • Neurons / drug effects*
  • Neurons / metabolism*
  • Phosphorylation / drug effects
  • Rats
  • Ribosomal Protein S6 Kinases / metabolism
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism*
  • Sirolimus / pharmacology


  • Amino Acid Transport Systems
  • Amino Acids, Branched-Chain
  • Immunosuppressive Agents
  • Ribosomal Protein S6 Kinases
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Leucine
  • Sirolimus