McHugh Patrick C, Rogers Geraldine R, Loudon Barbara, Glubb Dylan M, Joyce Peter R, Kennedy Martin A
Department of Pathology, University of Otago, Christchurch, New Zealand.
J Neurosci Res. 2008 Feb 1;86(2):306-16. doi: 10.1002/jnr.21482.
Antidepressant drugs can have significant effects on the mood of a patient suffering from major depression or other disorders. The pharmacological actions of these drugs generally affect the uptake or metabolism of the neurotransmitters serotonin, noradrenalin, and, to a lesser extent, dopamine. However, many aspects of antidepressant action are not understood. We conducted a proteomic analysis in a neuronal cell culture model in an attempt to identify molecules important to the operation of pathways functionally relevant to antidepressant action. The model involved generating cultures containing mixed neural and glial cells by controlled differentiation of mouse embryonic stem cells, followed by exposure to 1 microM paroxetine for 14 days. After antidepressant exposure, we observed increased expression or modification of sepiapterin reductase (SPR), heat shock protein 9A, RAS and EF-hand domain containing, and protein disulfide isomerase associated 3 and decreased expression or modification of creatine kinase, actin, prohibitin, a T-cell receptor alpha chain, defensin-related cryptdin 5, and the intermediate filament proteins glial fibrillary acidic protein and vimentin. SPR, the most strongly up-regulated protein observed, controls production of tetrahydrobiopterin, an essential cofactor for the synthesis of many neurotransmitters including serotonin, making it a plausible and intriguing candidate protein for involvement in mood control and antidepressant drug action. SPR and the other proteins identified may represent links to molecular processes of importance to mood dysregulation and control, and their respective genes may be novel candidates for the study of antidepressant pharmacogenetics.
抗抑郁药物对患有重度抑郁症或其他疾病的患者的情绪会产生显著影响。这些药物的药理作用通常会影响神经递质血清素、去甲肾上腺素的摄取或代谢，对多巴胺的影响程度较小。然而，抗抑郁作用的许多方面仍不为人所知。我们在神经元细胞培养模型中进行了蛋白质组学分析，试图确定对与抗抑郁作用功能相关的通路运作重要的分子。该模型包括通过小鼠胚胎干细胞的受控分化生成含有混合神经和胶质细胞的培养物，然后将其暴露于1微摩尔的帕罗西汀中14天。在抗抑郁药物暴露后，我们观察到蝶呤还原酶（SPR）、热休克蛋白9A、含RAS和EF-手结构域以及蛋白二硫键异构酶相关3的表达或修饰增加，而肌酸激酶、肌动蛋白、抑制素、T细胞受体α链、防御素相关隐窝蛋白5以及中间丝蛋白胶质纤维酸性蛋白和波形蛋白的表达或修饰减少。SPR是观察到的上调最强烈的蛋白质，它控制四氢生物蝶呤的产生，四氢生物蝶呤是包括血清素在内的许多神经递质合成所必需的辅因子，这使其成为参与情绪控制和抗抑郁药物作用的一个合理且引人入胜的候选蛋白质。SPR和其他鉴定出的蛋白质可能代表了与情绪失调和控制重要的分子过程的联系，它们各自的基因可能是抗抑郁药物遗传学研究的新候选基因。
