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  • The EMBO Journal (2004) 23, 1567 - 1575
  • doi:10.1038/sj.emboj.7600151

Published online: 18 March 2004

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

Xuejun Tian1, Takaya Gotoh1, Kiyoshi Tsuji2, Eng H Lo2, Su Huang1 and Larry A Feig1

  1. Department of Biochemistry, Tufts University School of Medicine, Boston, MA, USA
  2. Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital, Boston, MA, USA

Correspondence to:

Larry A Feig, Department of Biochemistry, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA. Tel.: +1 617 636 6867/6868; Fax: +1 617 636 2409; E-mail: larry.feig@tufts.edu

Received 18 September 2003; Accepted 10 February 2004

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.

  • Keywords:

    • calcium signaling,
    • NMDA glutamate receptors,
    • Ras,
    • Ras-GRF,
    • Sos
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