Dwivedi Yogesh, Rizavi Hooriyah S, Shukla Pradeep K, Lyons Jennifer, Faludi Gabor, Palkovits Miklos, Sarosi Andrea, Conley Robert R, Roberts Rosalinda C, Tamminga Carol A, Pandey Ghanshyam N
Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 W. Taylor Street, Chicago, IL 60612, USA.
Biol Psychiatry. 2004 Feb 1;55(3):234-43. doi: 10.1016/j.biopsych.2003.11.003.
We recently reported reduced [3H]cyclic adenosine monophosphate binding and catalytic activity of protein kinase A in prefrontal cortex of depressed suicide victims. Here we examined the molecular basis of these alterations and whether these findings can be replicated in another cohort.
Prefrontal cortex from depressed suicide victims and nonpsychiatric controls were obtained from the Lenhossek Human Brain Program, Budapest and the Maryland Brain Collection Program. [3H]cyclic adenosine monophosphate binding and protein kinase A activity were determined by radioligand binding and enzymatic assay, respectively. Expression of catalytic and regulatory subunits was determined by quantitative reverse transcription polymerase chain reaction and Western blot, respectively.
[3H]cyclic adenosine monophosphate binding and total and endogenous protein kinase A activity were significantly decreased in membrane and cytosol fractions of prefrontal cortex of depressed suicide victims from the Budapest cohort, with a similar magnitude (33%-40% reduction) as reported for the Maryland cohort. In both cohorts, selective reduction (36%-41%) in mRNA and protein expression of the regulatory RIIbeta and the catalytic Cbeta was observed.
Our results suggest abnormalities in [3H]cyclic adenosine monophosphate binding and catalytic activity kinase A in brain of depressed suicide victims, which could be due to reduced expression of RIIbeta and Cbeta. These abnormalities in PKA may be critical in the pathophysiology of depression.
我们最近报道了抑郁自杀受害者前额叶皮质中[3H]环磷酸腺苷结合及蛋白激酶A的催化活性降低。在此，我们研究了这些改变的分子基础，以及这些发现是否能在另一组人群中得到验证。
抑郁自杀受害者和非精神科对照者的前额叶皮质取自布达佩斯的Lenhossek人类脑计划和马里兰脑收集计划。[3H]环磷酸腺苷结合及蛋白激酶A活性分别通过放射性配体结合和酶促测定法进行测定。催化亚基和调节亚基的表达分别通过定量逆转录聚合酶链反应和蛋白质印迹法进行测定。
来自布达佩斯队列的抑郁自杀受害者前额叶皮质的膜和胞质溶胶部分中，[3H]环磷酸腺苷结合以及总蛋白激酶A和内源性蛋白激酶A活性显著降低，降低幅度（33%-40%）与马里兰队列报道的相似。在两个队列中，均观察到调节性RIIβ和催化性Cβ的mRNA和蛋白表达选择性降低（36%-41%）。
我们的结果表明，抑郁自杀受害者大脑中[3H]环磷酸腺苷结合及催化活性激酶A存在异常，这可能是由于RIIβ和Cβ表达降低所致。蛋白激酶A的这些异常可能在抑郁症的病理生理学中起关键作用。
