State-dependent Ras signaling and AMPA receptor trafficking

Genes Dev. 2005 Sep 1;19(17):2000-15. doi: 10.1101/gad.342205. Epub 2005 Aug 17.

Abstract

Synaptic trafficking of AMPA-Rs, controlled by small GTPase Ras signaling, plays a key role in synaptic plasticity. However, how Ras signals synaptic AMPA-R trafficking is unknown. Here we show that low levels of Ras activity stimulate extracellular signal-regulated kinase kinase (MEK)-p42/44 MAPK (extracellular signal-regulated kinase [ERK]) signaling, whereas high levels of Ras activity stimulate additional Pi3 kinase (Pi3K)-protein kinase B (PKB) signaling, each accounting for approximately 50% of the potentiation during long-term potentiation (LTP). Spontaneous neural activity stimulates the Ras-MEK-ERK pathway that drives GluR2L into synapses. In the presence of neuromodulator agonists, neural activity also stimulates the Ras-Pi3K-PKB pathway that drives GluR1 into synapses. Neuromodulator release increases with increases of vigilance. Correspondingly, Ras-MEK-ERK activity in sleeping animals is sufficient to deliver GluR2L into synapses, while additional increased Ras-Pi3K-PKB activity in awake animals delivers GluR1 into synapses. Thus, state-dependent Ras signaling, which specifies downstream MEK-ERK and Pi3K-PKB pathways, differentially control GluR2L- and GluR1-dependent synaptic plasticity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Histamine / pharmacology
  • In Vitro Techniques
  • Long-Term Potentiation
  • MAP Kinase Signaling System
  • Models, Neurological
  • Mutagenesis, Site-Directed
  • Neuronal Plasticity
  • Neurotransmitter Agents / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Receptors, AMPA / genetics
  • Receptors, AMPA / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction
  • Synapses / metabolism
  • ras Proteins / genetics
  • ras Proteins / metabolism*

Substances

  • Neurotransmitter Agents
  • Proto-Oncogene Proteins
  • Receptors, AMPA
  • Recombinant Fusion Proteins
  • Histamine
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • ras Proteins
  • glutamate receptor ionotropic, AMPA 2
  • glutamate receptor ionotropic, AMPA 1