Developmentally regulated role for Ras-GRFs in coupling NMDA glutamate receptors to Ras, Erk and CREB.
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.
Tian
Xuejun
X
Department of Biochemistry, Tufts University School of Medicine, Boston, MA, USA.
Gotoh
Takaya
T
Tsuji
Kiyoshi
K
Lo
Eng H
EH
Huang
Su
S
Feig
Larry A
LA
D000818:Animals; D000831:Animals, Newborn; D029681:Arabidopsis Proteins; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D020837:SOS1 Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D020521:Stroke / Q000378:metabolism / Q000473:pathology; D020663:ras Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*; D020666:ras-GRF1 / Q000235:genetics / Q000378:metabolism*
D029681:Arabidopsis Proteins; D017362:Cyclic AMP Response Element-Binding Protein; C504491:Rasgrf2 protein, mouse; D016194:Receptors, N-Methyl-D-Aspartate; D020837:SOS1 Protein; D020663:ras Guanine Nucleotide Exchange Factors; D020666:ras-GRF1; C406738:SOS2 protein, Arabidopsis; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins