Differential and brain region-specific regulation of rap-1 and Epac in depressed suicide victims
Differential and brain region-specific regulation of rap-1 and Epac in depressed suicide victims
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DOI：
10.1001/archpsyc.63.6.639
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发表时间：
2006-06-01
影响因子：
--
通讯作者：
Pandey, Ghanshyam N.
中科院分区：
文献类型：
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作者：
Dwivedi, Yogesh;Mondal, Amal C.;Pandey, Ghanshyam N.
背景：抑郁症是一个主要的公共卫生问题。尽管进行了多年的研究，但与抑郁症相关的分子机制仍不清楚。RAP-1在多种细胞外刺激下被激活，是蛋白激酶A的主要底物之一，参与脑内多种生理功能，包括细胞存活和突触可塑性。Rap-1也可以通过EPAC被环磷酸腺苷直接激活，从而参与不依赖于蛋白激酶A的生理功能的调节。目的：检测抑郁症的发病是否与Rap-1的激活和表达改变以及EPAC的表达有关。设计：死后研究。地点：组织来自匈牙利布达佩斯塞梅尔韦斯大学伦霍塞克人脑计划和马里兰精神病学研究中心的脑收集计划，参与者：28例抑郁症自杀者和28例非精神病对照组的死后脑。干预：脑组织检查。主要观察指标：RAP-1的激活以及RAP-1和EPAC在前额叶皮质、海马体和小脑的信使RNA和蛋白水平。结果：RAP-1的激活显著降低(P<；.001)在自杀组的前额叶皮质和海马。这与Rap-1信使RNA和蛋白质水平的显著降低有关(P<；.001)。相反，只有EPAC-2(P<；.001)而不是EPAC-1(P=.89)的蛋白水平在这些受试者的前额叶皮质和海马区显著增加。无论是将两个队列放在一起还是分开分析，这些变化都是存在的。结论：鉴于Rap-1在神经保护和突触可塑性中的重要性，我们对Rap-1和EPAC在不同脑区的差异调控的发现表明，这些分子在抑郁症的病理生理学中具有相关性。
Context: Depression is a major public health problem. Despite many years of research, the molecular mechanisms associated with depression remain unclear. Rap-1, activated in response to many extracellular stimuli, is one of the major substrates of protein kinase A, which participates in myriad physiologic functions in the brain, including cell survival and synaptic plasticity. Rap-1 is also activated directly by cyclic adenosine monophosphate through Epac, and thus participates in mediating physiologic functions independent of protein kinase A.Objective: To examine whether the pathogenesis of depression is associated with altered activation and expression of Rap-1, as well as expression of Epac, in depressed suicide victims.Design: Postmortem study.Setting: Tissues were obtained from the Lenhossek Human Brain Program, Semmelweis University, Budapest, Hungary, and the Brain Collection Program of the Maryland Psychiatric Research Center, Baltimore.Participants: Postmortem brains of 28 depressed suicide victims and 28 nonpsychiatric control subjects.Intervention: Examination of brain tissues.Main Outcome Measures: Rap-1 activation as well as messenger RNA and protein levels of Rap-1 and Epac in prefrontal cortex, hippocampus, and cerebellum.Results: Rap-1 activation was significantly reduced (P < .001) in prefrontal cortex and hippocampus in the suicide group. This was associated with significant reductions in Rap-1 messenger RNA and protein levels (P < .001). In contrast, protein level of only Epac-2 (P < .001) but not Epac-1 (P = .89) was significantly increased in prefrontal cortex and hippocampus of these subjects. These changes were present whether the 2 cohorts were analyzed together or separately. None of the measures showed any significant change in cerebellum in the suicide group.Conclusion: Given the importance of Rap-1 in neuroprotection and synaptic plasticity, our findings of differential regulation of Rap-1 and Epac between brain regions suggest the relevance of these molecules in the pathophysiology of depression.