Identification of a novel signaling pathway and its relevance for GluA1 recycling

Guiscard Seebohm, Sebastian Neumann, Carsten Theiss, Tanja Novkovic, Elaine V Hill, Jeremy M Tavaré, Florian Lang, Michael Hollmann, Denise Manahan-Vaughan, Nathalie Strutz-Seebohm

Research output: Contribution to journalArticle (Academic Journal)peer-review

19 Citations (Scopus)

Abstract

We previously showed that the serum- and glucocorticoid-inducible kinase 3 (SGK3) increases the AMPA-type glutamate receptor GluA1 protein in the plasma membrane. The activation of AMPA receptors by NMDA-type glutamate receptors eventually leads to postsynaptic neuronal plasticity. Here, we show that SGK3 mRNA is upregulated in the hippocampus of new-born wild type Wistar rats after NMDA receptor activation. We further demonstrate in the Xenopus oocyte expression system that delivery of GluA1 protein to the plasma membrane depends on the small GTPase RAB11. This RAB-dependent GluA1 trafficking requires phosphorylation and activation of phosphoinositol-3-phosphate-5-kinase (PIKfyve) and the generation of PI(3,5)P(2). In line with this mechanism we could show PIKfyve mRNA expression in the hippocampus of wild type C57/BL6 mice and phosphorylation of PIKfyve by SGK3. Incubation of hippocampal slices with the PIKfyve inhibitor YM201636 revealed reduced CA1 basal synaptic activity. Furthermore, treatment of primary hippocampal neurons with YM201636 altered the GluA1 expression pattern towards reduced synaptic expression of GluA1. Our findings demonstrate for the first time an involvement of PIKfyve and PI(3,5)P(2) in NMDA receptor-triggered synaptic GluA1 trafficking. This new regulatory pathway of GluA1 may contribute to synaptic plasticity and memory.
Original languageEnglish
Pages (from-to)e33889
JournalPLoS ONE
Volume7
Issue number3
DOIs
Publication statusPublished - 2012

Keywords

  • Animals
  • Hippocampus
  • Enzyme Inhibitors
  • Mice
  • Protein-Serine-Threonine Kinases
  • Phosphatidylinositol Phosphates
  • Aminopyridines
  • Heterocyclic Compounds, 3-Ring
  • Rats
  • RNA, Messenger
  • Animals, Newborn
  • Phosphorylation
  • rab GTP-Binding Proteins
  • Rats, Wistar
  • Immediate-Early Proteins
  • Mice, Inbred C57BL
  • Xenopus
  • Oocytes
  • Receptors, AMPA
  • Up-Regulation
  • Phosphotransferases (Alcohol Group Acceptor)
  • Receptors, N-Methyl-D-Aspartate
  • Signal Transduction

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