Kopnisky K L, Chalecka-Franaszek E, Gonzalez-Zulueta M, Chuang D-M
Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Building 10 Center Drive, Room 4C206, MSC 1363 Bethesda, MD 20892-1363, USA.
Neuroscience. 2003;116(2):425-35. doi: 10.1016/s0306-4522(02)00573-0.
The cyclic AMP response element binding protein (CREB) has major roles in mediating adaptive responses at glutamatergic synapses and in the neuroprotective effects of neurotrophins. CREB has been implicated as a potential mediator of antidepressant actions. In vitro, chronic lithium treatment has been shown to promote neuronal cell survival. In the present study, we have used cultures of cerebellar granule neurons to analyze the effects of acute and chronic lithium treatment on the response to toxic concentrations of glutamate. Such concentrations of glutamate decrease the phosphorylation of CREB at serine(133) in an N-methyl-D-aspartate (NMDA) receptor-dependent manner. Chronic, but not acute, lithium treatment suppresses glutamate-induced decreases in phosphorylated CREB, and transfection studies indicate that chronic lithium, in the presence of a glutamate stimulus, markedly increases CRE-driven gene expression. Experiments with selected pharmacological reagents indicate that the glutamate-induced decreases in phosphorylated CREB are regulated primarily by protein phosphatase 1. Chronic lithium treatment not only decreases protein phosphatase 1 activity under these circumstances, but also augments glutamate-induced increases in MEK activity. PD 98059, a MEK inhibitor, prevents chronic lithium treatment from increasing phosphorylated CREB levels in glutamate-treated neurons. We conclude from these results that chronic lithium treatment is permissive for maintaining higher phosphorylated CREB levels in the presence of glutamate in part by decreasing protein phosphatase 1 activity and in part by increasing MEK activity. Higher levels of phosphorylated CREB and CRE-responsive genes such as bcl-2 may be responsible for lithium's reported effects on neuronal survival.
环磷酸腺苷反应元件结合蛋白（CREB）在介导谷氨酸能突触的适应性反应以及神经营养因子的神经保护作用中发挥着主要作用。CREB被认为是抗抑郁作用的潜在介导因子。在体外，慢性锂治疗已被证明可促进神经元细胞存活。在本研究中，我们使用小脑颗粒神经元培养物来分析急性和慢性锂治疗对谷氨酸毒性浓度反应的影响。这种谷氨酸浓度以N-甲基-D-天冬氨酸（NMDA）受体依赖性方式降低CREB丝氨酸（133）位点的磷酸化。慢性而非急性锂治疗可抑制谷氨酸诱导的磷酸化CREB减少，转染研究表明，在谷氨酸刺激存在的情况下，慢性锂可显著增加CRE驱动的基因表达。使用选定的药理学试剂进行的实验表明，谷氨酸诱导的磷酸化CREB减少主要受蛋白磷酸酶1调节。慢性锂治疗不仅在这些情况下降低蛋白磷酸酶1活性，还增强谷氨酸诱导的MEK活性。MEK抑制剂PD 98059可阻止慢性锂治疗增加谷氨酸处理神经元中磷酸化CREB的水平。我们从这些结果得出结论，慢性锂治疗在谷氨酸存在的情况下允许维持较高的磷酸化CREB水平，部分原因是通过降低蛋白磷酸酶1活性，部分原因是通过增加MEK活性。较高水平的磷酸化CREB和CRE反应基因（如bcl-2）可能是锂对神经元存活所报道作用的原因。
