Lithium and valproic acid treatments reduce PKC activation and receptor-G protein coupling in platelets of bipolar manic patients
Lithium and valproic acid treatments reduce PKC activation and receptor-G protein coupling in platelets of bipolar manic patients
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DOI：
10.1016/j.jpsychires.2004.10.007
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发表时间：
2005-07-01
影响因子：
4.8
通讯作者：
Friedman, E
中科院分区：
文献类型：
--
作者：
Hahn, CG;Umapathy;Friedman, E
蛋白激酶 C (PKC) 分布和激活失调以及受体-G 蛋白偶联异常与双相情感障碍 (BID) 的病理生理学有关。锂的治疗效果还与其减少 PKC 激活和 G 蛋白介导的信号传导的能力相关。我们检查了正常对照、BD 躁狂症或精神分裂症患者在未治疗状态下以及服用锂或丙戊酸后的血小板中 PKC 和受体-G 蛋白偶联的细胞分布和激活情况。在基础和50nM佛波醇12-肉豆蔻酸酯、13-乙酸酯(PMA)、1μM血清素或0.5U/ml凝血酶刺激条件下测量PKC活性。 G 蛋白与血清素或凝血酶受体的偶联通过血清素或凝血酶介导的 [S-35]GTP gamma S 与膜 G α 蛋白的结合来评估。结果表明，BD 躁狂症患者中膜相关的 PKC 活性和刺激诱导的 PKC 易位增加，而精神分裂症患者中刺激引起的 PKC 易位减弱。给药两周后，锂和丙戊酸治疗可将刺激诱导的 PKC 易位减弱到类似程度，并降低细胞质和膜部分中的 PKC 活性。在 BID 躁狂症患者中检测到 5-HT 或凝血酶刺激的 [S-35]GTP gamma S 与 Got 蛋白的结合增加，但在精神分裂症患者中未检测到，尽管基础 [S-35]GTP gamma S 结合在各诊断组之间没有差异。锂和丙戊酸治疗在相当的时间过程中同样减少了受体-G 蛋白偶联。因此，锂或丙戊酸治疗可以缓解 BD 躁狂症患者血小板中膜相关 PKC、胞质至膜 PKC 易位和受体 G 蛋白偶联的增加。 (c) 2004 Elsevier Ltd. 保留所有权利。
Dysregulated protein kinase C (PKC) distribution and activation, and abnormal receptor-G protein coupling, have been implicated in the pathophysiology of bipolar affective disorder (BID). The therapeutic effectiveness of lithium has also been correlated with its ability to reduce PKC activation and G protein-mediated signaling. We examine the cellular distribution and activation of PKC and receptor-G protein coupling in blood platelets from normal controls, patients with BD mania or schizophrenia during treatment-free state, and after lithium or valproic acid administration. PKC activity was measured under basal and 50 nM phorbol 12-myristate, 13-acetate (PMA), I mu M serotonin or 0.5 U/ml thrombin-stimulated conditions. The coupling of G proteins to serotonin or thrombin receptors were assessed by serotonin or thrombin-mediated [S-35]GTP gamma S binding to membrane G alpha proteins. The results demonstrate that membrane-associated PKC activity and stimulus-induced PKC translocation are increased in BD manic, whereas stimulus-elicited PKC translocation is attenuated in schizophrenic patients. Lithium and valproic acid treatments attenuated the stimulus-induced PKC translocations to a similar degree and decreased PKC activity in both cytosolic and membranous fractions after two weeks of drug administration. An increase in 5-HT or thrombin stimulated [S-35]GTP gamma S binding to Got proteins was detected in BID manic but not in schizophrenic patients although basal [S-35]GTP gamma S binding was not different across the diagnostic groups. Lithium and valproic acid treatments similarly reduced receptor-G protein coupling with comparable time courses. Thus, increased membrane-associated PKC, cytosol to membrane PKC translocation and receptor-G protein coupling in platelets of BD manic patients were alleviated by lithium or valproic acid treatments. (c) 2004 Elsevier Ltd. All rights reserved.