Pacheco M A, Stockmeier C, Meltzer H Y, Overholser J C, Dilley G E, Jope R S
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham 35294-0017, USA.
Brain Res. 1996 Jun 3;723(1-2):37-45. doi: 10.1016/0006-8993(96)00207-7.
The function of the phosphoinositide signal transduction system and the levels of heterotrimeric G-protein alpha-subunits were examined in postmortem prefrontal cortex regions (8/9) and region (10) from suicide victims with major depression and matched control subjects without psychiatric illness. The hydrolysis of [3H]phosphatidylinositol (PI) stimulated by phospholipase C, GTP-gamma-S, NaF, and neurotransmitter receptor agonists was measured in membrane preparations from both groups. Phospholipase C-beta activity was similar in depressed suicide and control subjects in the two regions of prefrontal cortex. In prefrontal cortex (10), but not in (8/9), the GTP-gamma-S concentration-dependent stimulation of [3H]PI hydrolysis was significantly lower (30%) in the depressed suicide group compared to the control group. Receptor-coupled, G-protein-mediated [3H]PI hydrolysis induced with carbachol, histamine, trans-1-aminocyclopentyl-1, 3-dicarboxylic acid (ACPD, a glutamatergic metabotropic receptor agonist), serotonin, or 2-methylthio-adenosine triphosphate (2mATP, a purinergic receptor agonist) in the presence of GTP-gamma-S stimulated equivalent responses in the two groups of subjects in each brain region. In prefrontal cortex (10) there was a 68% increase in the level of the 45 kDa subtype of G alpha s and in prefrontal cortex (8/9) there was a significant decrease (21%) in the level of G alpha i2 in the depressed suicide group compared to the control group. Levels of other heterotrimeric G-protein alpha-subunits (G alpha q/11, G alpha i1, and G alpha o) were not different in depressed suicide and control subjects in either brain region. Moreover, there were no differences in the levels of phospholipase C-beta or protein kinase C-alpha in the two groups of subjects in either brain region examined. These results demonstrate that in the prefrontal cortex of suicide victims with major depression compared to normal control subjects there is a region-specific alteration of G-protein-induced activation of the phosphoinositide signal transduction system and in the levels of G-protein alpha-subunits involved in cyclic AMP synthesis. These findings provide direct evidence in human brain that these two important signal transduction systems are altered in suicide subjects with major depression.
在患有重度抑郁症的自杀受害者以及无精神疾病的匹配对照组受试者的尸检前额叶皮质区域（8/9区）和10区，对磷酸肌醇信号转导系统的功能以及异源三聚体G蛋白α亚基的水平进行了检测。在两组的膜制剂中，测量了磷脂酶C、GTP-γ-S、NaF和神经递质受体激动剂刺激下的[3H]磷脂酰肌醇（PI）水解情况。在额叶前皮质的两个区域，抑郁自杀组和对照组的磷脂酶C-β活性相似。在额叶前皮质10区而非8/9区，与对照组相比，抑郁自杀组中GTP-γ-S浓度依赖性的[3H]PI水解刺激显著降低（30%）。在GTP-γ-S存在的情况下，由卡巴胆碱、组胺、反式-1-氨基环戊基-1,3-二羧酸（ACPD，一种谷氨酸能代谢型受体激动剂）、5-羟色胺或2-甲硫基三磷酸腺苷（2mATP，一种嘌呤能受体激动剂）诱导的受体偶联、G蛋白介导的[3H]PI水解在每个脑区的两组受试者中刺激产生了等效反应。与对照组相比，抑郁自杀组额叶前皮质10区Gαs的45 kDa亚型水平增加了68%，额叶前皮质8/9区Gαi2水平显著降低（21%）。在两个脑区中，抑郁自杀组和对照组的其他异源三聚体G蛋白α亚基（Gαq/11、Gαi1和Gαo）水平没有差异。此外，在所检测的两个脑区中，两组受试者的磷脂酶C-β或蛋白激酶C-α水平也没有差异。这些结果表明，与正常对照组受试者相比，患有重度抑郁症的自杀受害者的前额叶皮质中，G蛋白诱导的磷酸肌醇信号转导系统激活以及参与环磷酸腺苷合成的G蛋白α亚基水平存在区域特异性改变。这些发现为人类大脑中这两个重要的信号转导系统在患有重度抑郁症的自杀受试者中发生改变提供了直接证据。
