Unlap M T, Jope R S
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham 35294-0017, USA.
Neuropsychopharmacology. 1997 Jul;17(1):12-7. doi: 10.1016/S0893-133X(97)00020-1.
This investigation tested if lithium, the primary therapeutic agent for bipolar mood disorder, modulated activation of the AP-1 transcription factor in PC12 cells treated with nerve growth factor (NGF), which induces robust responses in these cells. NGF induced large, time-dependent increases in AP-1 DNA binding activity. Pretreatment with 5 mmol/L lithium for 24 h reduced AP-1 induction by NGF by 42%; shorter treatments and lower concentrations of lithium had smaller inhibitory effects on AP-1. This effect of lithium was not limited to AP-1, as it also inhibited NGF-induced cyclic AMP responsive element (CRE) DNA binding activity. In contrast, activation of AP-1 and CRE by forskolin was unaffected by lithium. AP-1 constituent proteins were differentially susceptible to lithium, as cJun was reduced by 55%, cFos was unaffected by lithium, and an intermediate effect was observed with Jun B. These results reveal that lithium modulates the activation of transcription factors in a neuronal cell model, indicating that selective regulation of gene expression may contribute to the long term in vivo effect of lithium.
本研究检测了双相情感障碍的主要治疗药物锂是否能调节经神经生长因子（NGF）处理的PC12细胞中AP-1转录因子的激活，NGF可在这些细胞中诱导强烈反应。NGF诱导AP-1 DNA结合活性出现大量的、时间依赖性增加。用5 mmol/L锂预处理24小时可使NGF诱导的AP-1降低42%；较短时间的处理和较低浓度的锂对AP-1的抑制作用较小。锂的这种作用并不局限于AP-1，因为它还抑制NGF诱导的环磷酸腺苷反应元件（CRE）DNA结合活性。相比之下，福斯高林对AP-1和CRE的激活不受锂的影响。AP-1组成蛋白对锂的敏感性不同，cJun减少了55%，cFos不受锂的影响，Jun B则表现出中等程度的影响。这些结果表明，锂在神经元细胞模型中调节转录因子的激活，表明基因表达的选择性调节可能有助于锂在体内的长期作用。
