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（改编自申请人摘要）：双相情感障碍的病理生理学