Tian Xuejun, Gotoh Takaya, Tsuji Kiyoshi, Lo Eng H, Huang Su, Feig Larry A
Department of Biochemistry, Tufts University School of Medicine, Boston, MA, USA.
EMBO J. 2004 Apr 7;23(7):1567-75. doi: 10.1038/sj.emboj.7600151. Epub 2004 Mar 18.
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.
p140 Ras-GRF1和p130 Ras-GRF2构成了一个钙/钙调蛋白调节的鸟嘌呤核苷酸交换因子家族，该家族可激活Ras GTP酶。对缺乏这些交换因子的小鼠的研究表明，p140 Ras-GRF1和p130 Ras-GRF2都能将NMDA谷氨酸受体（NMDARs）与成年小鼠皮质神经元中Ras/Erk信号级联的激活以及CREB转录因子活性的维持联系起来。与Ras-GRFs的这一功能以及CREB活性已知的神经保护作用一致，成年Ras-GRF基因敲除小鼠大脑中缺血诱导的CREB激活减少，神经元损伤增强。有趣的是，在新生动物的皮质神经元中，NMDARs通过Sos而非Ras-GRF交换因子发出信号，这意味着Ras-GRFs赋予了NMDARs成熟神经元特有的功能。
