PROTEIN KINASES--MOLECULAR ROLES IN PRODUCING BEHAVIOR

蛋白质激酶——产生行为的分子作用

• 批准号: 6639426
• 负责人: JAMES SCHWARTZ
• 金额: $ 34.1万
• 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: 1992-01-07 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6639426
• 关键词: Aplysia; actins; antisense nucleic acid; behavioral habituation /sensitization; complementary DNA; enzyme activity; genetic translation; laboratory rabbit; molecular cloning; neural facilitation; oligonucleotides; polyadenylate; protein kinase A; serotonin; sirolimus; synaptosomes; tissue /cell culture; ubiquitin

DESCRIPTION: (from applicant'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 molecular genetics and biochemically-oriented neurophysiology indicate an underlying synaptic malady. Long-term presynaptic facilitation (LTF) of sensory-to-motor neuron synapses, which is a form of plasticity underlying behavioral sensitization in the marine mollusk Aplysia and an elementary form of learning, can be produced by the action of the cAMP-dependent protein kinase (PKA). Ubiquitin-proteasome-mediated degradation of PKA regulatory R-subunits occurs in sensory neurons when treated to produce long-term facilitation; this molecular change endures only if new protein is made. No change in catalytic (C) subunits occurs. A decreased R/C ratio produces a kinase that is more sensitive to subsaturating cAMP and sets the baseline extent of protein phosphorylation within the neuron at a higher level for at least 24h. The fine control of cAMP-dependent phosphorylation is mediated by regulated proteolysis through the ubiquitin-proteasome pathway, which degrades R subunits selectively. This pathway is up-regulated by the induction of the immediate early gene Ap -ubiquitin C terminal hydrolase, which enhances proteolysis by the proteasome. Our first aim is to identify the coupling and ligating enzymes (E2 and E3) that specifically ubiquitinate R subunits and to determine whether they are induced during LTF. Why does PKA remain persistently active long after LTF has been induced? Evidence suggests the regulation of protein synthesis locally at synapses. We will test the idea that the persistent kinase is required to produce proteins needed for augumented translation as well as cytoskeletal proteins for the growth of new synapses.

描述：（从申请人的摘要中） 在分子水平上研究突触功能的重要性最多是 明显地了解心理和神经系统疾病 心理药理治疗学，现代分子遗传学和 以生化为导向的神经生理学表示潜在的突触疾病。 感觉到运动神经元突触的长期突触前促进（LTF）， 这是海军陆战队中行为敏化的一种可塑性形式 软体动物的Aplysia和一种基本的学习形式可以由 依赖CAMP的蛋白激酶（PKA）的作用。 PKA调节R-subunits的泛素 - 蛋白酶体介导的降解发生 在接受长期促进的感觉神经元中；这 仅当制造新蛋白质时，分子变化才能忍受。催化没有变化 （c）亚基发生。 R/C比下降会产生更多的激酶 对饱和营的敏感并设置蛋白质的基线范围 神经元内的磷酸化至少至少24小时。很好 控制cAMP依赖性磷酸化的控制是由调节的蛋白水解介导的 通过泛素 - 蛋白酶体途径，它降低了R亚基 有选择地。该途径被立即诱导而上调 早期基因AP-泛素C末端水解酶，从而增强了蛋白水解 蛋白酶体。我们的第一个目的是识别耦合和连接酶 （e2和e3）特别泛素化r亚基并确定是否是否 它们是在LTF期间诱导的。为什么PKA很久以后保持持久活跃 LTF已被诱导？有证据表明蛋白质合成的调节 在突触中本地。我们将测试持续性激酶的想法 需要产生八月翻译所需的蛋白质以及 新突触生长的细胞骨架蛋白。