PROTEIN KINASE C IN MANIA & IN LITHIUM'S ACTIONS

躁狂症中的蛋白激酶 C

• 批准号: 3384808
• 负责人: EITAN FRIEDMAN
• 金额: $ 15.56万
• 依托单位: ALLEGHENY UNIVERSITY OF HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-05-01 至 1994-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3384808
• 关键词: biomarker; bipolar depression; bipolar depression manic phase; brain metabolism; drug interactions; drug metabolism; enzyme mechanism; human subject; lithium; mental disorder chemotherapy; phosphoproteins; platelets; protein kinase C; psychopharmacology; serotonin inhibitor

Lithium's clinical utility in treating affective disorders is well established. However, the relevant pharmacological mechanism(s) for these actions of the ion have not been elucidated. Numerous previous reports have described the effects of lithium on various serotonergic and other neurotransmitter mechanisms. Recent investigations have suggested that the clinical effects of lithium may be mediated by the ion's ability to inhibit the dephosphorylation of inositol-1-phosphate and thus antagonize phosphatidylinositol hydrolysis which is a signal transduction system shared by various neurotransmitters and hormones. Investigations performed in our laboratory have documented the effect of lithium on brain serotonin release and on the role of protein kinase C (PKC) in modulating serotonin release. In preliminary studies, we have observed that lithium can inhibit (1) PKC-stimulated serotonin release in brain and platelets and (2) PKC stimulation induced translocation of the enzyme in brain and platelets. These studies also indicate that platelet PKC subcellular distribution and manic patients are markedly different from controls. In the proposed investigation, we plan to (1) examine platelet serotonin release and irs modulation by PKC stimulation in patients with affective disorders, (2) measure platelet protein kinase C activity, its subcellular distribution and its response to serotonergic and other stimuli in subjects diagnosed as having affective disorders, and (3) examine the relationship between clinical response to lithium and its effects on the above platelet serotonin and PKC markers. The studies aim to (1) explore the possibility that PKC is a biological marker for mania and (2) test the hypothesized relationship between lithium's therapeutic action in affective disorders and its effects on phosphorylation mediated by PKC.

锂在治疗情感障碍方面的临床效用良好 已确立的。 然而，相关的药理机制 离子的这些作用尚未得到阐明。 很多的 之前的报告描述了锂对各种疾病的影响 血清素能和其他神经递质机制。 最近的 研究表明，锂的临床效果 可能是由离子抑制的能力介导的 1-磷酸肌醇去磷酸化，从而拮抗 磷脂酰肌醇水解是一种信号转导 由各种神经递质和激素共享的系统。 我们实验室进行的调查记录了 锂对大脑血清素释放的影响及其作用 蛋白激酶 C (PKC) 调节血清素释放。 在 初步研究，我们观察到锂可以抑制 (1) PKC 刺激大脑和血小板中的血清素释放，以及 (2) PKC 刺激诱导大脑中酶的易位 血小板。 这些研究还表明血小板 PKC 亚细胞分布与躁狂患者明显不同 来自控制。 在拟议的调查中，我们计划 (1) 通过 PKC 检查血小板血清素释放和 IRS 调节 情感障碍患者的刺激，（2）测量 血小板蛋白激酶C活性及其亚细胞分布 及其对受试者血清素能和其他刺激的反应 被诊断患有情感障碍，并且 (3) 检查 对锂的临床反应与其效果之间的关系 关于上述血小板血清素和 PKC 标记物。 研究目的 (1) 探讨 PKC 作为生物标志物的可能性 狂热和（2）测试锂之间的假设关系 情感障碍的治疗作用及其对 PKC 介导的磷酸化。