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Analysis of opioid receptors and substance P activity in signal transduction and inflammation

阿片受体和 P 物质在信号转导和炎症中的活性分析

基本信息

批准号：
13671615
负责人：
NISHIMURA Kinya
金额：
$ 1.34万
依托单位：
JUNTENDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

We found an endogenous factor that modulated enkephalin-degrating activity and purified it from bovine spinal cord based on its inhibitory activity toward enkephalin-degrading enzymes. Structural analysis revealed the factor to be Leu-Val-Tyr-Pro-Trp-Thr and it was named spinorphin. It has been found that spinorphin inhibited the activity toward various enkephalin-degrating enzymes from monkey brain, especially dipeptidyl peptidase III. Recently we found that this inhibitory significantly inhibited bradykin-induced nociceptive flexor responses. We also have reported roles for spinorphin in inflammation. Spinorphin significantly inhibited the functions of polymorphonuclear neutrophils by suppressing the binding of fMLF to its receptor on PMNs. The possible role of spinorphin as reglulators in pain and inflammation will be discussed.G protein coupled receptor kinases (GRKs) phosphorylate agonist-occupied G protein-coupled receptors, leading to receptor desensitization. We investigated whether human substance P receptor is a substrate of GRK5. We report that human Substance P receptor is phosphorylated by purified GRK5. The phosphorylation has a high stoichiometry and a low Km. These data provide the first evidence that human substance P receptor is a substrate of GRK5.Although the importance of Ach in the learning and memory processes has been point out in the stratum as well as the cerebral cortex. The aim of our study was to answer this question using the striatal cholinergic inter-neurons and to elucidate the mechanism of synaptic plasticity in them. The results obtained here indicate the following. Electrical stimulation of cortico/thalamostriatal pathway frequently evokes a depolarizing and hyperpolarizing postsynaptic potential in the cholinergic inter-neurons that is composed of a cortic/thalamostriatal glutamatergic EPSP and an intrastriatally evoked disynaptic GABAergic IPSP, respectively.

我们发现了一种调节脑啡肽降解活性的内源性因子，并根据其对脑啡肽降解酶的抑制活性从牛脊髓中纯化了它。结构分析表明该因子为Leu-Val-Tyr-Pro-Trp-Thr，命名为Spin。已发现Spin抑制猴脑内各种脑啡肽降解酶的活性，尤其是二肽基肽酶III的活性。最近我们发现这种抑制作用显著地抑制了缓激肽诱导的伤害性屈肌反应。我们还报道了Spin在炎症中的作用。Spinogin通过抑制中性粒细胞表面FMLF与其受体的结合，显著抑制中性粒细胞的功能。将讨论Spin作为调节剂在疼痛和炎症中的可能作用。G蛋白偶联受体激酶(GRKs)使激动剂占据的G蛋白偶联受体磷酸化，导致受体脱敏。我们研究了人P物质受体是否是GRK5的底物。我们报道了人的P物质受体被纯化的GRK5磷酸化。磷酸化具有高的化学计量比和低的Km。这些数据首次提供了人类P物质受体是GRK5底物的证据，尽管Ach在学习和记忆过程中的重要性已经在大脑皮层和层中被指出。本研究的目的是用纹状体胆碱能中间神经元来回答这个问题，并阐明它们的突触可塑性的机制。这里得到的结果表明了以下几点。电刺激皮质/丘脑-纹状体通路经常在胆碱能中间神经元中诱发去极化和超极化突触后电位，该电位分别由皮质/丘脑纹状体谷氨酸能EPSP和纹状体内诱发的双突触GABA能IPSP组成。