Zhuravliova E, Barbakadze T, Narmania N, Sepashvili M, Mikeladze D G
Department of Biochemistry, I. Beritashvili Institute of Physiology, Tbilisi, Georgia.
Neurochem Res. 2009 Jun;34(6):1076-82. doi: 10.1007/s11064-008-9877-4. Epub 2008 Nov 11.
Recent observations have established that interruption of insulin production causes deficits in learning and memory formation. We have studied the mechanism of insulin's neuroprotective effect on primary neuronal cells and in streptozotocin (STZ)-induced diabetic rat brain. We have found that in hippocampal neuronal cells insulin increases the content of farnesylated Ras and phosphorylated form of Akt. Besides, the treatment of cells by insulin leads to the activation of mitochondrial cytochrome oxidase, which is inhibited by manumycin, a farnesyltransferase inhibitor. During experimental diabetes, the content of membrane-bound GRF1 was decreased in rat hippocampus that was correlated with the reduction in mitochondrial Ras and phosphorylated forms of Akt. This redistribution in Ras-GRF system was accompanied by the alteration in the activities of CREB, NF-kB (p65) and c-Rel transcription factors. We have proposed that hypoinsulinemia induces the inhibition of Ras signalling in the neuronal cells additionally by abnormality of Ras trafficking into mitochondria.
最近的观察结果表明，胰岛素分泌中断会导致学习和记忆形成方面的缺陷。我们研究了胰岛素对原代神经元细胞以及链脲佐菌素（STZ）诱导的糖尿病大鼠大脑的神经保护作用机制。我们发现，在海马神经元细胞中，胰岛素会增加法尼基化Ras的含量以及Akt的磷酸化形式。此外，用胰岛素处理细胞会导致线粒体细胞色素氧化酶的激活，而法尼基转移酶抑制剂曼诺霉素会抑制这种激活。在实验性糖尿病期间，大鼠海马中膜结合型GRF1的含量降低，这与线粒体Ras和Akt磷酸化形式的减少相关。Ras-GRF系统的这种重新分布伴随着CREB、NF-κB（p65）和c-Rel转录因子活性的改变。我们提出，低胰岛素血症通过Ras向线粒体转运异常，额外诱导神经元细胞中Ras信号传导的抑制。
