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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Animals, Newborn
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Arabidopsis Proteins
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Cells, Cultured
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Cyclic AMP Response Element-Binding Protein / genetics
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Cyclic AMP Response Element-Binding Protein / metabolism*
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Enzyme Activation
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Extracellular Signal-Regulated MAP Kinases / genetics
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Extracellular Signal-Regulated MAP Kinases / metabolism*
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Mice
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Mice, Knockout
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Neurons / cytology
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Neurons / metabolism
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Receptors, N-Methyl-D-Aspartate / genetics
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Receptors, N-Methyl-D-Aspartate / metabolism*
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SOS1 Protein / genetics
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SOS1 Protein / metabolism
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Signal Transduction / physiology*
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Stroke / metabolism
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Stroke / pathology
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ras Guanine Nucleotide Exchange Factors / genetics
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ras Guanine Nucleotide Exchange Factors / metabolism*
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ras Proteins / metabolism*
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ras-GRF1 / genetics
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ras-GRF1 / metabolism*
Substances
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Arabidopsis Proteins
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Cyclic AMP Response Element-Binding Protein
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Rasgrf2 protein, mouse
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Receptors, N-Methyl-D-Aspartate
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SOS1 Protein
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ras Guanine Nucleotide Exchange Factors
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ras-GRF1
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SOS2 protein, Arabidopsis
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Protein Serine-Threonine Kinases
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Extracellular Signal-Regulated MAP Kinases
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ras Proteins