PROTEIN KINASE C IN MANIA & IN LITHIUM'S ACTIONS

锂在治疗情感障碍方面的临床效用很好 已经成立了。然而，相关的药理机制(S) 因为离子的这些作用还没有阐明。数不胜数 以前的报道已经描述了锂对各种疾病的影响 5-羟色胺能和其他神经递质机制。近期 研究表明，锂的临床疗效 可能是由离子抑制的能力介导的 肌醇-1-磷酸去磷酸化从而拮抗 磷脂酰肌醇水解是一种信号转导 由各种神经递质和荷尔蒙共享的系统。 在我们实验室进行的调查记录了 锂对脑内5-羟色胺释放的影响及其作用 蛋白激酶C(PKC)在调节5-羟色胺释放中的作用在……里面 初步研究发现，锂能抑制(1) PKC刺激脑和血小板释放5-羟色胺及(2) PKC刺激诱导脑内酶移位和 血小板。这些研究还表明，血小板蛋白激酶C 亚细胞分布与躁狂症患者明显不同 从控件。在拟议的调查中，我们计划(1) 检测PKC对血小板5-羟色胺释放和IRS的调节作用 情感性精神障碍患者的刺激：(2)测量 血小板蛋白激酶C活性及其亚细胞分布 以及它对5-羟色胺能和其他刺激的反应 被诊断为患有情感障碍，以及(3)检查 锂的临床疗效与疗效的关系 上述血小板5-羟色胺和蛋白激酶C标志物。研究的目的是 为了(1)探讨PKC作为一种生物标记物的可能性 狂热和(2)检验锂元素之间的假设关系 情感性精神障碍的治疗作用及其对疾病的影响 PKC介导的磷酸化。

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.