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

Xuejun Tian1, Takaya Gotoh, Kiyoshi Tsuji

  • 1Department of Biochemistry, Tufts University School of Medicine, Boston, MA, USA.

The EMBO Journal
|March 19, 2004
PubMed

Insights

Ras-GRF1 and Ras-GRF2 are crucial guanine-nucleotide exchange factors that link NMDA glutamate receptors to Ras/Erk signaling in adult brain neurons. Their absence impairs CREB activation and increases neuronal damage, highlighting their neuroprotective role.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Signaling

Background:

  • Ras-GRF1 and Ras-GRF2 are calcium/calmodulin-regulated guanine-nucleotide exchange factors.
  • These factors activate Ras GTPases, crucial for cellular signaling pathways.

Purpose of the Study:

  • To investigate the role of Ras-GRF1 and Ras-GRF2 in coupling NMDA glutamate receptors (NMDARs) to downstream signaling in adult cortical neurons.
  • To determine the impact of Ras-GRF deficiency on CREB activity and neuronal survival following ischemic conditions.

Main Methods:

  • Utilized knockout mouse models lacking p140 Ras-GRF1 and p130 Ras-GRF2.
  • Examined the activation of Ras/Erk signaling cascade and CREB transcription factor activity in cortical neurons.
  • Assessed neuronal damage and CREB activation following ischemia.

Main Results:

  • Ras-GRF1 and Ras-GRF2 were found to couple NMDARs to Ras/Erk signaling and CREB activity in adult cortical neurons.
  • Mice lacking Ras-GRFs showed reduced ischemia-induced CREB activation and enhanced neuronal damage.
  • Neonatal neurons utilized Sos, not Ras-GRFs, for NMDAR signaling, suggesting a developmental switch.

Conclusions:

  • Ras-GRFs play a critical role in mature neuronal function by mediating NMDAR-dependent signaling to Ras/Erk and CREB.
  • Ras-GRFs are essential for neuroprotection against ischemic injury through CREB-mediated pathways.
  • The signaling pathway downstream of NMDARs differs between neonatal and adult neurons, with Ras-GRFs being specific to mature neurons.

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