PROTEIN KINASES--MOLECULAR ROLES IN PRODUCING BEHAVIOR

蛋白质激酶——产生行为的分子作用

• 批准号: 2267480
• 负责人: JAMES SCHWARTZ
• 金额: $ 10.39万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-01-07 至 1996-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2267480
• 关键词: Aplysia; alternatives to animals in research; behavioral habituation /sensitization; molecular psychobiology; neural facilitation; neurochemistry; neurons; phosphorylation; protein kinase A; protein metabolism; proteolysis; synapses; ubiquitin

DESCRIPTION (Investigator's Abstract): The importance of studying synaptic function at the molecular level is most obvious for understanding mental and neurological diseases where psychopharmacological therapeutics, modern moleculargenetics and biochemically oriented neuropathology suggest an underlying synaptic malady. Long-term presynaptic facilitation, which is a form of synaptic plasticity underlying behavioral sensitization in the marine mollusk, Aplysia, and an elementary form of learning, can be produced by the action ofthe cAMP-dependent protein kinase (PKA).A decrease of 20-50 percent in the regulatory (R) subunits of PKA occurs in sensory nerve cells when stimulated to produce long-term facilitation; this molecular change is sustainedonly if new protein is made. No change in catalytic (C) subunits occurs. A decreased R/C ratio would be expected to produce a kinase more sensitiveto subsaturating levels of cAMP: the change in R/C sets the baseline extent of protein phosphorylation in the neuron at a higher level. How is this fine control of cAMP-dependent phosphorylation achieved? There is no changein the levels of PKA subunit mRNA in sensory cells that have been facilitated, rather R subunit protein is selectively degraded. The first aim of the present application is to characterize the mechanisms causing turnover of R biochemically. Preliminary studies suggest that R subunits are degraded by ubiquitin-mediated proteolysis. It is likely that this process is enhanced degradation. The second aim is to identify the factor(s) that enhance degradation of R subunits in sensory neurons that have received stimuli which produce long-term facilitation. The first set of experiments proposed is designed to show definitively that R subunits are ubiquitinated and then to characterize the proteolytic mechanism involved. The second set of experiments is designed to determine what factors target the degradation of the R subunits. Specifically targeted proteolysis may be a general mechanism for generating the persistent protein phosphorylation common to other forms of long- termsynaptic plasticity. A similar mechanism is thought to degrade selectively other proteins that regulate cell division, cancer, cell growth and determination of body shape. If correct, this idea is a further indication that similar molecular mechanisms are used both in learning and in development.

描述（研究者的摘要）：研究突触的重要性 分子层的功能对于理解心理最为明显 以及心理药理治疗，现代的神经系统疾病 分子基因和以生化为导向的神经病理学表明 潜在的突触疾病。 长期突触前促进，这是 一种突触可塑性在行为敏感的基础上的形式 海洋软体动物，Aplysia和一种基本的学习形式，可以是 由CAMP依赖性蛋白激酶（PKA）的作用产生 PKA的调节（R）亚基中的20-50％发生在感觉中 神经细胞刺激以产生长期促进；这 如果制造新蛋白质，则分子变化会持续。 没有变化 发生催化（C）亚基。 R/C比率下降将有望 产生激酶更敏感的营地水平：变化 在R/C中，神经元中蛋白质磷酸化的基线范围 更高的水平。 这种依赖营地磷酸化的精细控制如何 实现了？ 在感觉中，PKA亚基mRNA的水平没有变化 已经促进的细胞，而是R亚基蛋白是有选择的 退化。 本应用的第一个目的是表征 在生物化学上引起R流失的机制。初步研究表明 该R亚基被泛素介导的蛋白水解降解。 这是 这个过程可能会增强降解。 第二个目标是 确定增强感觉中R亚基降解的因素 接受刺激的神经元可产生长期促进。 提出的第一组实验旨在确定地表明 r亚基是泛素化的，然后表征蛋白水解 涉及的机制。第二组实验旨在确定 哪些因素是针对R亚基的降解的。 具体来说 靶向蛋白水解可能是产生的一般机制 持续的蛋白质磷酸化与其他形式的长期磷酸化 术语突触可塑性。 人们认为类似的机制会降低 有选择地调节细胞分裂，癌症，细胞生长的其他蛋白质 并确定身体形状。 如果正确的话，这个想法是进一步的 迹象表明在学习和 在开发中。