SIGNAL TRANSDUCTION IN BIPOLAR ILLNESS

双相情感障碍中的信号转导

• 批准号: 6392713
• 负责人: EITAN FRIEDMAN
• 金额: $ 7.26万
• 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 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6392713
• 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（改编自申请人的摘要）：双极的病理生理学 情感障碍（不良）尚不清楚，尽管它的症状可能是 有效地用锂离子和其他情绪稳定剂处理。在这两个中 动物和人类研究，我们观察到锂会损害激活 蛋白激酶C（PKC）的酶，该酶由受体介导的刺激 二酰基甘油的形成并催化许多重要的 神经元蛋白。在利用血小板和验尸大脑的研究中 从不良受试者中，我们注意到膜相关的PKC和 酶响应细胞表面的易位 受体。作为了解理解基本机制的一部分 这些变化，我们检查了受体介导的膜G蛋白的激活 在坏主题中。 5-羟色胺受体和G蛋白之间的增强耦合 在坏的大脑中发现。这些结果表明，改变的影响 特征不好的可能与夸张的跨大脑有关 在一个或多个神经递质途径中发出信号，锂发作 通过抑制受体引发的跨膜信号流的治疗作用。 拟议的调查的目的是继续检验假设 这种不良与增强的G蛋白介导的跨膜信号传导和 情绪稳定的药物会引起。通过他们的治疗功效 减少G蛋白偶联引发的信号的转导 神经递质受体。具体而言，在提出的实验中，我们计划 （1）直接评估不良受试者的死后大脑区域， 5-羟色胺和A肾上腺素能受体与G蛋白的偶联均可 基础和受体刺激条件并探索潜在机制 这可能会导致大脑不良耦合的改变，（2）定义 有助于膜相关的高程的特定机制 PKC活动不好。为此，我们计划调查机架I蛋白表达 以及大脑不良的钙蛋白酶和激活的钙蛋白酶水平。我们也将（3） 在不良受试者中评估血小板G蛋白功能和PKC活性 在AN_ATTEMPT中的情绪稳定药物治疗期间，以进一步测试 这些参数是治疗反应的标记。