SIGNAL TRANSDUCTION IN BIPOLAR ILLNESS

双相情感障碍中的信号转导

• 批准号: 6042274
• 负责人: EITAN FRIEDMAN
• 金额: $ 24.8万
• 依托单位: MCP HAHNEMANN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-15 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6042274
• 关键词: G protein; alpha adrenergic receptor; biological signal transduction; bipolar depression; brain; enzyme activity; human therapy evaluation; human tissue; lithium; mental disorder chemotherapy; pathologic process; platelets; postmenopause; postmortem; protein kinase C; receptor coupling; serotonin receptor

DESCRIPTION (adapted from applicant's abstract): The pathophysiology of bipolar affective disorder (BAD) is not well understood, although its symptoms can be effectively treated with lithium ion and other mood stabilizing agents. In both animal and human studies, we have observed that lithium impairs the activation of protein kinase C (PKC), an enzyme that is stimulated by receptor-mediated formation of diacylglycerol and catalyzes the phosphorylation of many important neuronal proteins. In studies utilizing both platelets and postmortem brains from BAD subjects, we have noted increases in both membrane- associated PKC and in translocation of the enzyme in response to stimulation of cell surface receptors. As part of an attempt to understand the underlying mechanism for these changes, we examined receptor-mediated activation of membrane G proteins in BAD subjects. Enhanced coupling between serotonin receptors and G proteins was found in brains of BAD. These results suggest that the altered affect that characterizes BAD may be associated with an exaggerated transinembrane signaling in one or more neurotransmitter pathways and that lithium exerts its therapeutic action by suppressing receptor initiated transmembrane signal flow. The aim of the proposed investigation is to continue to test the hypothesis that BAD is related to enhanced G protein-mediated transmembrane signaling and that the mood stabilizing drugs elicit . t their therapeutic efficacy by reducing the transduction of signals initiated by G protein-coupled neurotransmitter receptors. Specifically, in the proposed experiments we plan to (1) directly assess in postmortem brain regions of BAD subjects, the coupling of serotonin and a, adrenergic receptors to G proteins both under basal and receptor stimulated conditions and explore the potential mechanisms which may contribute to the altered coupling in BAD brains and (2) define the specific mechanisms which contribute to the elevation in membrane associated PKC activity BAD. To this end we plan to investigate RACK I protein expression as well as calpain and activated calpain levels in BAD brains. We will also (3) assess platelet G protein functions and PKC activity in BAD subjects before and during treatment with mood stabilizing drugs in an_attempt to further test these parameters as markers of therapeutic response.

描述(摘自申请者摘要)：双相情感障碍的病理生理学 情感障碍(BAD)目前还不清楚，尽管其症状可能是 用锂离子和其他情绪稳定剂有效治疗。在这两个地方 动物和人类的研究，我们已经观察到锂削弱了激活 蛋白激酶C(PKC)，一种由受体介导的刺激酶 二酰甘油的形成和催化许多重要的磷酸化 神经元蛋白质。在利用血小板和死后大脑进行的研究中 从不良受试者中，我们注意到膜相关蛋白激酶C和 在响应细胞表面刺激的酶的移位中 感受器。作为试图理解以下基本机制的一部分 在这些变化中，我们研究了受体介导的膜G蛋白的激活 在不好的科目里。5-羟色胺受体与G蛋白的偶联作用增强 在坏人的大脑中被发现。这些结果表明，这些改变会影响 不良的特征可能与夸张的跨膜有关 在一个或多个神经递质通路中的信号传递，以及锂在 抑制受体启动的跨膜信号流的治疗作用。 拟议的调查的目的是继续检验这一假设 BAD与增强的G蛋白介导的跨膜信号和 稳定情绪的药物所引发的。通过测试他们的治疗效果 减少G蛋白偶联引发的信号转导 神经递质受体。具体地说，在拟议的实验中，我们计划 为了(1)直接评估不良受试者的死后脑区， 5-羟色胺和肾上腺素能受体与G蛋白的偶联 基础刺激和受体刺激条件及其可能机制的探讨 这可能有助于坏大脑中改变的耦合和(2)定义 膜相关膜升高的特定机制 PKC活动不正确。为此，我们计划研究Rack I蛋白的表达 以及坏大脑中的钙蛋白酶和激活的钙蛋白酶水平。我们还将(3) 评估不良受试者的血小板G蛋白功能和蛋白激酶C活性 在治疗期间服用稳定情绪的药物，试图进一步测试 这些参数可作为治疗反应的标志。