Gary D S, Mattson M P
Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, Baltimore, Maryland 21224, USA.
J Neurochem. 2001 Mar;76(5):1485-96. doi: 10.1046/j.1471-4159.2001.00173.x.
Integrins are integral membrane proteins that mediate adhesive interactions of cells with the extracellular matrix and with other cells. Integrin engagement results in activation of intracellular signaling cascades that effect several different cellular responses including motility, proliferation and survival. Although integrins are known to provide cell survival signaling in various types of non-neuronal cells, the possibility that integrins modulate neuron survival has not been explored. We now report data demonstrating a neuroprotective function of integrins in embryonic hippocampal neurons. Neurons grown on laminin, an integrin ligand, exhibit increased resistance to glutamate-induced apoptosis compared with neurons grown on polylysine. Neurons expressed integrin beta1 and treatment of cultures with an antibody against integrin beta1 abolished the protective effect of laminin. Neurons maintained on laminin exhibited a sustained activation of the Akt signaling pathway demonstrated in immunoblot analyses using an antibody that selectively recognizes phosphorylated Akt. The neuroprotective effect of integrin engagement by laminin was mimicked by an IKLLI-containing integrin-binding peptide and was abolished by treatment of neurons with the PI3 kinase inhibitor wortmanin. Levels of the anti-apoptotic protein Bcl-2 were increased in neurons grown on laminin and decreased by wortmanin, suggesting a mechanism for the neuroprotective effect of integrin-mediated signaling. The ability of integrin-mediated signaling to prevent glutamate-induced apoptosis suggests a mechanism whereby neuron-substrate interactions can promote neuron survival under conditions of glutamate receptor overactivation.
整合素是整合膜蛋白，介导细胞与细胞外基质以及其他细胞之间的黏附相互作用。整合素的结合会导致细胞内信号级联反应的激活，从而影响几种不同的细胞反应，包括运动性、增殖和存活。尽管已知整合素在各种类型的非神经元细胞中提供细胞存活信号，但整合素调节神经元存活的可能性尚未得到探索。我们现在报告的数据表明整合素在胚胎海马神经元中具有神经保护功能。与在聚赖氨酸上生长的神经元相比，在整合素配体层粘连蛋白上生长的神经元对谷氨酸诱导的凋亡具有更高的抗性。神经元表达整合素β1，用抗整合素β1抗体处理培养物可消除层粘连蛋白的保护作用。在层粘连蛋白上维持培养的神经元在使用选择性识别磷酸化Akt的抗体进行免疫印迹分析中显示出Akt信号通路的持续激活。层粘连蛋白与整合素结合产生的神经保护作用可被含IKLLI的整合素结合肽模拟，并用PI3激酶抑制剂渥曼青霉素处理神经元可消除该作用。在层粘连蛋白上生长的神经元中抗凋亡蛋白Bcl-2的水平升高，而渥曼青霉素可使其降低，这表明了整合素介导的信号传导产生神经保护作用的机制。整合素介导的信号传导防止谷氨酸诱导的凋亡的能力提示了一种机制，即神经元与底物的相互作用可以在谷氨酸受体过度激活的条件下促进神经元存活。
