SIGNAL TRANSDUCTION IN BIPOLAR ILLNESS

双相情感障碍中的信号转导

• 批准号: 6542327
• 负责人: EITAN FRIEDMAN
• 金额: $ 19.05万
• 依托单位: CITY COLLEGE OF NEW YORK
• 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 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6542327
• 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）：双相情感障碍的病理生理学 尽管情感障碍 (BAD) 的症状可以通过 用锂离子和其他情绪稳定剂有效治疗。在两者中 在动物和人类研究中，我们观察到锂会损害激活 蛋白激酶 C (PKC)，一种受受体介导刺激的酶 形成二酰基甘油并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的研究中 从 BAD 受试者中，我们注意到膜相关 PKC 和 酶因细胞表面刺激而易位 受体。作为尝试理解潜在机制的一部分 这些变化，我们检查了受体介导的膜 G 蛋白激活 在糟糕的科目中。增强血清素受体和 G 蛋白之间的耦合 在 BAD 的大脑中发现。这些结果表明，改变的影响 表征 BAD 可能与夸大的跨膜有关 一种或多种神经递质途径中的信号传递，并且锂发挥其作用 通过抑制受体启动的跨膜信号流来发挥治疗作用。 拟议调查的目的是继续检验假设 BAD 与 G 蛋白介导的跨膜信号传导增强有关 即情绪稳定药物引起的。 t 其治疗效果 减少 G 蛋白偶联引发的信号转导 神经递质受体。具体来说，在拟议的实验中，我们计划 (1) 直接评估 BAD 受试者死后的大脑区域， 血清素和a，肾上腺素能受体与G蛋白的偶联均在 基础和受体刺激条件并探索潜在机制 这可能会导致 BAD 大脑中耦合的改变，并且 (2) 定义 有助于膜相关升高的特定机制 PKC 活动不好。为此我们计划研究 RACK I 蛋白表达 以及 BAD 大脑中的钙蛋白酶和激活的钙蛋白酶水平。我们还将（3） 在 BAD 受试者之前和之前评估血小板 G 蛋白功能和 PKC 活性 在使用情绪稳定药物治疗并尝试进一步测试期间 这些参数作为治疗反应的标志。