Ciani Elisabetta, Guidi Sandra, Bartesaghi Renata, Contestabile Antonio
Department of Biology, University of Bologna, Italy.
J Neurochem. 2002 Sep;82(5):1282-9. doi: 10.1046/j.1471-4159.2002.01080.x.
Nitric oxide (NO) is a small, diffusible, highly reactive molecule with a dichotomous regulatory role in the brain: an intra- and intercellular messenger under physiological conditions and a neurodegenerative agent under pathological conditions. We have recently demonstrated that long-lasting exposure to an neuronal nitric oxide synthase (nNOS) inhibitor down-regulated serine/threonine kinase (Akt) survival pathway and caused apoptosis in cerebellar granule cell cultures. The present study further substantiates the role of NO in neuronal survival by demonstrating that blocking its production down-regulates the activity of cAMP-responsive element binding protein (CREB), a transcription factor involved in cell survival and synaptic plasticity. Pharmacological dissection of the pathway linking NO to CREB shows that cGMP and its kinase are intermediate effectors. We also identify Bcl-2 as one of the anti-apoptotic genes down-regulated by NO shortage and decreased CREB phosphorylation. These results not only confirm the role of CREB in neuronal survival but also provide circumstantial evidence for a novel link among NO, CREB activation and survival.
一氧化氮（NO）是一种体积小、可扩散、反应性高的分子，在大脑中具有双重调节作用：在生理条件下作为细胞内和细胞间信使，在病理条件下作为神经退行性变因子。我们最近证明，长期暴露于神经元型一氧化氮合酶（nNOS）抑制剂会下调丝氨酸/苏氨酸激酶（Akt）生存途径，并导致小脑颗粒细胞培养物中的细胞凋亡。本研究通过证明阻断NO的产生会下调环磷酸腺苷反应元件结合蛋白（CREB）的活性，进一步证实了NO在神经元存活中的作用，CREB是一种参与细胞存活和突触可塑性的转录因子。对连接NO与CREB的途径进行药理学剖析表明，环磷酸鸟苷（cGMP）及其激酶是中间效应物。我们还确定Bcl-2是因NO缺乏和CREB磷酸化减少而下调的抗凋亡基因之一。这些结果不仅证实了CREB在神经元存活中的作用，还为NO、CREB激活和存活之间的新联系提供了间接证据。
