SIGNAL TRANSDUCTION IN BIPOLAR ILLNESS

描述（改编自申请人摘要）：双相情感障碍的病理生理学 情感性精神障碍（BAD）还没有得到很好的理解，尽管它的症状可以是 用锂离子和其他情绪稳定剂有效治疗。无论是 在动物和人体研究中，我们观察到锂损害了 蛋白激酶C（PKC），一种由受体介导的 形成甘油二酯，并催化许多重要的 神经元蛋白在利用血小板和死后大脑的研究中， 在BAD受试者中，我们注意到膜相关PKC和 在响应细胞表面刺激的酶移位中 受体。作为试图了解潜在机制的一部分， 这些变化，我们研究了受体介导的膜G蛋白的激活 不好的科目。5-羟色胺受体和G蛋白之间的增强偶联 在BAD的大脑中发现。这些结果表明，改变影响， BAD的特征可能与过度跨膜 在一个或多个神经递质通路中的信号传导，并且锂发挥其 通过抑制受体引发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这一假设 BAD与增强的G蛋白介导的跨膜信号传导有关， 情绪稳定药物引起的反应测试其疗效， 减少由G蛋白偶联启动的信号转导 神经递质受体具体来说，在我们计划的实验中， （1）直接评估BAD受试者的死后脑区， 5-羟色胺和α-肾上腺素能受体与G蛋白的偶联， 基础和受体刺激条件下，并探讨潜在的机制 这可能有助于改变BAD大脑中的耦合和（2）定义 有助于膜相关升高的特定机制 PKC活性差。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。我们也将（3） 评估BAD患者术前和术后血小板G蛋白功能和PKC活性， 在使用情绪稳定药物治疗期间， 这些参数作为治疗反应的标志。

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.