PROTEIN KINASE C IN MANIA & IN LITHIUM'S ACTIONS

锂在治疗情感性精神障碍方面的临床效用很好 确立了习 然而，相关药理学机制 离子的这些作用尚未阐明。 许多 先前的报道已经描述了锂对各种 肾上腺素能和其他神经递质机制。 最近 研究表明，锂的临床效果 可能是由离子的能力，以抑制 肌醇-1-磷酸的去磷酸化，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。 在我们的实验室进行的调查已经记录了 锂对脑5-羟色胺释放的影响以及锂在脑内的作用 蛋白激酶C（PKC）在调节5-羟色胺释放中的作用。 在 初步研究，我们观察到锂可以抑制（1） PKC刺激的脑和血小板中5-羟色胺释放和（2） PKC刺激诱导脑内酶移位， 血小板 这些研究还表明，血小板PKC 亚细胞分布和躁狂患者有明显不同 从控制。 在拟议的调查中，我们计划（1） 通过PKC检测血小板5-羟色胺释放和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 以及其对受试者中的肾上腺素能和其他刺激的反应 被诊断为患有情感障碍，以及（3）检查 锂盐的临床反应与其作用的关系 对上述血小板血清素和PKC标记物的影响。 研究目的 （1）探讨PKC作为一种生物学标志物的可能性， 躁狂症和（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。

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.