CAMP AND PHOSPHATASE CASCADE AND LTP

CAMP 和磷酸酶级联和 LTP

• 批准号: 2635757
• 负责人: EMMANUEL Manuel LANDAU
• 金额: $ 17.67万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-02-01 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2635757
• 关键词: FK506; calcineurin; calmodulin; cyclic AMP; enzyme activity; hippocampus; laboratory rat; long term potentiation; neurons; neuropharmacology; phosphatase inhibitor; phosphoprotein phosphatase; protein kinase C; synapses; FK506; calcineurin; calmodulin; cyclic AMP; enzyme activity; hippocampus; laboratory rat; long term potentiation; neurons; neuropharmacology; phosphatase inhibitor; phosphoprotein phosphatase; protein kinase C; synapses

DESCRIPTION: (Applicant's Abstract) Long-term potentiation (LTP) is a cellular memory process which is the focus of intense interest. Most attention has so far been devoted to the role of synaptic kinases in this process. In view of the burgeoning interest in the cellular role of phosphatases, the place of these enzymes in the mechanism of LTP is of great relevance. As has been shown in a recent publication from our group, postsynaptic phosphatases act as a gate for LTP, which is controlled by the cAMP pathway. The postsynaptic phosphatases are arranged in a cascade involving calcineurin, protein phosphatase 1 (PP1) and inhibitory protein 1 (I-1). I-1 is the point where the cascade is inhibited by cAMP. In the present application it is proposed to further define the phosphatase cascade involved in LTP, by applying specific inhibitors of calcineurin and PP1, as well as biochemically measuring the phosphorylation of I-1 after high frequency synaptic stimulation (HFS). It is also proposed to investigate the mechanism for the influence of stimulation pattern on the cAMP-dependence of LTP which may be mediated by postsynaptic accumulation of calmodulin. Finally, the role of phosphatases and cAMP in the maintenance phase of LTP will be studied. The proposed experiments are based on a detailed and testable model, and on solid preliminary data. The importance of LTP for understanding memory processes, the fundamental importance of placing postsynaptic phosphatases in the theoretical framework for LTP, and the ubiquity and importance of cAMP signaling in the brain, all lend significance to the proposed project.

描述：（申请人的摘要）长期增强（LTP）是 蜂窝记忆过程，这是强烈关注的重点。 最多 到目前为止，人们一直致力于突触激酶的作用 过程。 鉴于人们对细胞作用的兴趣 磷酸酶，这些酶在LTP机理中的位置很大 关联。 正如我们小组最近出版物所显示的那样 突触后磷酸酶充当LTP的门，该门由 营地。 突触后磷酸酶排列在级联 涉及钙调蛋白，蛋白质磷酸酶1（PP1）和抑制蛋白1 （I-1）。 I-1是营地抑制级联的点。 在 目前的应用建议进一步定义磷酸酶级联 参与LTP，通过应用钙调神经酶和PP1的特定抑制剂AS 以及在高后I-1的生化测量I-1的磷酸化 频率突触刺激（HFS）。 还建议调查 刺激模式影响的机制 LTP的营地依赖性可能是由突触后积累介导的 钙调蛋白。 最后，磷酸酶和cAMP在维护中的作用 LTP的阶段将进行研究。 提出的实验基于 详细且可测试的模型，以及固体初步数据。 重要性 LTP的理解记忆过程，这是基本的重要性 将突触后磷酸酶放置在LTP的理论框架中， 大脑中营地信号的无处不在和重要性，全部借给 对拟议项目的意义。