PROTEIN KINASES--MOLECULAR ROLES IN PRODUCING BEHAVIOR

蛋白质激酶——产生行为的分子作用

• 批准号: 2674344
• 负责人: JAMES SCHWARTZ
• 金额: $ 10.81万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-04-01 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2674344
• 关键词: Aplysia; alternatives to animals in research; cyclic AMP; enhancer binding protein; enzyme activity; immunologic assay /test; laboratory rabbit; memory; molecular psychobiology; neural facilitation; neural plasticity; neurogenetics; phosphorylation; proteasome; protein biosynthesis; protein kinase A; protein kinase C; serotonin; translation factor; ubiquitin

DESCRIPTION (Adapted from applicant's abstract): This is a request for a Senior Scientist Award. The importance of studying synaptic function at the molecular level is most obvious for understanding mental and neurological diseases where psychopharmacology and modern molecular genetics suggest an underlying synaptic malady. Long-term presynaptic facilitation (LTF) of sensory-to-motor synapses, which is a form of plasticity underlying behavioral sensitization in the marine mollusk Aplysia, is a convenient experimental model for understanding the molecular events that underlie memory storage. Two major protein kinases, cAMP-dependant protein kinase (PKA) and protein kinase C (PKC), operate to bring about LTF. These enzymes function in the complex mechanisms that bridge the induction and consolidation phases of memory, first by promoting new gene expression needed for the ultimate consolidation, and second by maintaining the stimulated neuron in an interim facilitated state. Thus, during the development of LTF, persistant protein phosphorylation results in the enhancement of synaptic strength by increasing the output of neurotransmitter at existing synapses; later, the memory is consolidated by normal output of transmitter at an increased number of new synapses. Both PKA and PKC induce new protein synthesis through phosphorylations that lead to the activation of transcription factors, including ApC/EBP (the homolog of vertebrate C/EBPbeta. We now aim to characterize how PKC phosphorylation regulates the ongoing cascade of new protein synthesis that is the molecular basis of memory storage in LTF. We find that the ubiquitin-mediated degradation of ApC/EBP is controlled by PKC protein phosphorylation(s), and that the regulatory (R) subunits of PKA decrease in sensory neurons due to ubiquitin-mediated proteolysis. A decreased R/C ratio produces a kinase more sensitive to subsaturating cAMP and sets the baseline extent of protein phosphorylation within the neuron at a higher level for at least 24 h; this change could be the molecular mechanism underlying an intermediary form of memory. Our working idea is that signal transduction by facilitating transmitter (e.g., serotonin) activates PKA, which then triggers a molecular cascade in the nucleus involving cAMP-reactive elements for transcription activator proteins and effector proteins, one or more of which alter the ubiquitin-proteasome in sensory neurons.

描述（根据申请人的摘要改编）：这是对 高级科学家奖。 在研究突触功能的重要性 分子水平对于理解心理和神经系统是最明显的 心理药理学和现代分子遗传学的疾病表明 潜在的突触疾病。 长期突触前促进（LTF） 感觉到运动突触，这是一种可塑性的形式 海洋软体动物Aplysia中的行为敏化是一个方便的 了解基于分子事件的实验模型 内存存储。 两个主要蛋白激酶，依赖CAMP的蛋白激酶 （PKA）和蛋白激酶C（PKC），可实现LTF。 这些酶 在桥接感应和 记忆的合并阶段，首先是通过促进新基因表达 最终合并所需的需要，其次是维护 在临时促进状态下刺激神经元。 因此，在 LTF的发展，持续蛋白磷酸化导致 通过增加输出的增强突触强度的增强 现有突触的神经递质；后来，记忆通过 发射器的正常输出在增加的新突触数量增加。 两个都 PKA和PKC通过磷酸化诱导新的蛋白质合成 转录因子的激活，包括APC/EBP（同源物 脊椎动物C/EBPBETA。 现在，我们旨在表征PKC磷酸化的方式 调节正在进行的新蛋白质合成的级联 LTF中存储器存储的基础。 我们发现泛素介导 APC/EBP的降解由PKC蛋白磷酸化控制，并且 由于PKA的调节（R）亚基，由于 泛素介导的蛋白水解。 降低的R/C比产生激酶 对饱和营地更敏感，并设置蛋白质的基线范围 神经元内的磷酸化至少24小时；这 变化可能是中介形式的分子机制 记忆。 我们的工作想法是通过促进信号转导 递质（例如5-羟色胺）激活PKA，然后触发分子 涉及cAMP反应元件的核中的级联 激活蛋白和效应蛋白，其中一种或多种改变 感觉神经元中的泛素 - 蛋白酶体。

项目成果

Translocation of protein kinase Cs in Aplysia neurons: evidence for complex regulation.

海兔神经元中蛋白激酶 C 的易位：复杂调节的证据。

• DOI: 10.1016/0169-328x(94)90134-1
• 发表时间: 1994
• 期刊: Brain research. Molecular brain research
• 作者: Sossin,WS;Schwartz,JH
• 通讯作者: Schwartz,JH

Persistent activation of cAMP-dependent protein kinase by regulated proteolysis suggests a neuron-specific function of the ubiquitin system in Aplysia.

通过调节蛋白水解作用持续激活 cAMP 依赖性蛋白激酶表明海兔中泛素系统具有神经元特异性功能。

• DOI: 10.1523/jneurosci.15-11-07592.1995
• 发表时间: 1995
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience.
• 作者: Chain,DG;Hegde,AN;Yamamoto,N;Liu-Marsh,B;Schwartz,JH
• 通讯作者: Schwartz,JH

Structure and expression of the Aplysia polyubiquitin gene.

海兔多聚泛素基因的结构和表达。

• DOI: 10.1016/s0169-328x(00)00021-8
• 发表时间: 2000
• 期刊: Brain research. Molecular brain research
• 作者: Hegde,AN;Broome,BM;Qiang,M;Schwartz,JH
• 通讯作者: Schwartz,JH

Stereochemistry of the Aplysia neuronal 12-lipoxygenase: specific potentiation of FMRFamide action by 12(S)-HPETE.

海兔神经元 12-脂氧合酶的立体化学：12(S)-HPETE 对 FMRFamide 作用的特异性增强。

• DOI: 10.1016/0006-8993(95)00375-z
• 发表时间: 1995
• 期刊: Brain research
• 影响因子: 2.9
• 作者: Abe,M;Klein,M;Steel,DJ;Thekkuveettil,A;Shapiro,E;Schwartz,JH;Feinmark,SJ
• 通讯作者: Feinmark,SJ

The many dimensions of cAMP signaling.

cAMP 信号传导的多个维度。

• DOI: 10.1073/pnas.251533998
• 发表时间: 2001
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Schwartz,JH