Abnormalities in protein kinase C signaling and the pathophysiology of bipolar disorder.
Abnormalities in protein kinase C signaling and the pathophysiology of bipolar disorder.
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DOI：
10.1034/j.1399-5618.1999.010204.x
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发表时间：
1999-12-01
影响因子：
5.4
通讯作者：
Friedman, E
中科院分区：
文献类型：
--
作者：
Hahn, C G;Friedman, E
蛋白激酶C（PKC）是一组钙和磷脂依赖性酶，在细胞信号转导系统中起着关键作用。最近积累的证据表明，PKC活性的改变在双相情感障碍的病理生理学中起着重要作用。许多实验室研究了情绪稳定剂对双相情感障碍患者、动物和培养细胞中PKC活性调节的影响。慢性锂治疗后，PKC激活显着减少，在大鼠大脑中，测量细胞质PKC的易位到膜室，或定量结合的PKC配体，PDBu。在培养的细胞中也证明了治疗浓度的锂在减弱PKC依赖性细胞内参数中的作用。更重要的是，双相情感障碍患者在躁狂状态时血小板PKC的改变也被发现。与重度抑郁症、精神分裂症或健康对照患者相比，躁狂症患者的PKC活性显著增加，表明PKC的变化可能是疾病特异性标志物。有趣的是，在躁狂症期间增强的PKC活性在情绪稳定剂治疗后随着躁狂症状的改善而被抑制。在平行的血小板中的结果，尸检研究表明，膜相关的PKC和刺激诱导的胞浆酶易位到膜也增加了双相患者的额叶皮层。其他研究表明双相情感障碍中其他信号转导机制的改变。这些包括G蛋白活化、磷脂酰肌醇（PI）信号传导、环AMP形成和细胞内钙稳态的改变。在双相情感障碍中PKC活性的改变可能与这些其他细胞内信号机制的变化有关。另外，PKC活性的变化可能是疾病的核心病理。需要更多的研究，以进一步表征PKC的变化与双相情感障碍的关联，使用适当的神经元模型。
Protein kinase C (PKC) is a group of calcium and phospholipid-dependent enzymes, which plays a pivotal role in cell signaling systems. Recently accumulated evidence indicates that alterations in PKC activity play a significant role in the pathophysiology of bipolar disorder. A number of laboratories investigated the effect of mood stabilizers on the regulation of PKC activity in bipolar patients, in animals, and in cultured cells. Following chronic lithium treatment, PKC activation was significantly reduced in rat brains, as measured by the translocation of cytoplasmic PKC to the membrane compartment, or by quantitative binding of the PKC ligand, PDBu. The effect of the therapeutic concentration of lithium in attenuating PKC-dependent intracellular parameters was also demonstrated in cultured cells. More importantly, alterations in platelet PKC was shown in bipolar patients during the manic state of the illness. In comparison to patients with major depressive disorder, schizophrenia, or healthy controls, PKC activity was significantly increased in manic patients, suggesting that changes in PKC may be an illness-specific marker. Interestingly, enhanced PKC activity during mania was suppressed following mood-stabilizer treatment as manic symptoms improved. In parallel to the findings in platelets, postmortem studies demonstrate that membrane-associated PKC and stimulation-induced translocation of cytosolic enzyme to the membrane were also increased in frontal cortex of bipolar patients. Other studies suggest alterations in other signal transduction mechanisms in bipolar disorder. These include alterations in G protein activation, phosphatidylinositol (PI) signaling, cyclic AMP formation, and intracellular calcium homeostasis. The alterations of PKC activity in bipolar disorder may be related to changes in these other intracellular signaling mechanisms. Alternatively, the changes of PKC activity may be the core pathology of the illness. More studies are required to further characterize the association of PKC changes with bipolar disorder, using a proper neuronal model.