Developmentally regulated role for Ras-GRFs in coupling NMDA glutamate receptors to Ras, Erk and CREB

EMBO J. 2004 Apr 7;23(7):1567-75. doi: 10.1038/sj.emboj.7600151. Epub 2004 Mar 18.

Abstract

p140 Ras-GRF1 and p130 Ras-GRF2 constitute a family of calcium/calmodulin-regulated guanine-nucleotide exchange factors that activate the Ras GTPases. Studies on mice lacking these exchange factors revealed that both p140 Ras-GRF1 and p130 Ras-GRF2 couple NMDA glutamate receptors (NMDARs) to the activation of the Ras/Erk signaling cascade and to the maintenance of CREB transcription factor activity in cortical neurons of adult mice. Consistent with this function for Ras-GRFs and the known neuroprotective effect of CREB activity, ischemia-induced CREB activation is reduced in the brains of adult Ras-GRF knockout mice and neuronal damage is enhanced. Interestingly, in cortical neurons of neonatal animals NMDARs signal through Sos rather than Ras-GRF exchange factors, implying that Ras-GRFs endow NMDARs with functions unique to mature neurons.

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
  • Animals, Newborn
  • Arabidopsis Proteins
  • Cells, Cultured
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Mice
  • Mice, Knockout
  • Neurons / cytology
  • Neurons / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • SOS1 Protein / genetics
  • SOS1 Protein / metabolism
  • Signal Transduction / physiology*
  • Stroke / metabolism
  • Stroke / pathology
  • ras Guanine Nucleotide Exchange Factors / genetics
  • ras Guanine Nucleotide Exchange Factors / metabolism*
  • ras Proteins / metabolism*
  • ras-GRF1 / genetics
  • ras-GRF1 / metabolism*

Substances

  • Arabidopsis Proteins
  • Cyclic AMP Response Element-Binding Protein
  • Rasgrf2 protein, mouse
  • Receptors, N-Methyl-D-Aspartate
  • SOS1 Protein
  • ras Guanine Nucleotide Exchange Factors
  • ras-GRF1
  • SOS2 protein, Arabidopsis
  • Protein Serine-Threonine Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • ras Proteins