The role of neuropeptide reseptor and its antagonists

许多调节肽已经从自然来源中分离出来并进行了测序。此外，基因技术领域的最新进展导致了对多肽前体分子结构的确定。基于已知的前体和成熟肽结构的信息，某些特定设计的合成肽使得研究受体结合的分子基础和多肽的活性作用成为可能。调节肽及其类似物的合成复制和由其前体衍生的多肽片段为我们提供了产生区域特异性抗体的重要免疫原。最近发现的新的调节肽，如PACAP(垂体腺苷环化酶激活肽)和甘丙素，使人们对神经元操作的控制和生理有了新的认识。我们需要通过研究它们的受体配体结合部位的结构来推进我们的知识，偶联…本研究的目的是探讨神经肽受体及其拮抗剂的作用机制。1.合成了几个与人促胰液素前体相关的多肽。通过测定胰腺的体积流量来比较合成肽在大鼠和狗身上的效力。大的分泌素(分泌素-41)的效力大约是猪分泌素-27的三分之一。用促胰液素-41作为免疫原，制备抗大促胰液素血清，作为检测脑促胰液素(Chey，Mochizuki，Yanaihara)的工具。2.我们给出了各种PACAP片段，试图寻找选择性的PACAP拮抗剂。结果表明，PACAP(5-38)和PACAP(10-38)对PACAP-38的受体结合、[Ca~(2+)]i升高和VIP释放均有明显的拮抗作用。另一方面，PACAP(1-15)能部分拮抗PACAP引起的豚鼠远端结肠氯的分泌，而PACAP(1-15)不能阻断VIP诱发的豚鼠结肠VIP反应(科威特原)。4.[D-Trp^8]Galanin(1-15)ol是特异性甘丙肽受体的激动剂。提示[D-Trp^8]Galanin(1-15)ol可能是开发新型甘丙素拮抗剂的关键化合物。5.研究了中药提取物对CCK受体的影响。在所研究的提取物中，Saiko提取物的低相对分子质量部分显示与CCK-B受体结合。结果表明，Saiko提取物中可能含有CCK激动剂或拮抗剂(Gardner、Brown、wei、Yanaihara)，说明人工合成的多肽片段对研究神经肽受体及其拮抗剂的作用具有重要意义。较少

A number of regulatory peptides have been isolated from natural sources and sequenced. In addition, recent advances in the field of gene technology have resulted in a burst of determination about the molecular structure of the peptide precursors. Based on the known information about precursor and mature peptide structures, certain purpose-designed synthetic peptides have enabled the investigation of such questions as the molecular basis of receptor binding and the active roles of peptides. Synthetic replicates of regulatory peptides and their analogs and peptide fragments derived from their precursors provide us with important immunogens for producting region-specific antibodies. The recent discovery of novel regulatory peptides such as PACAP (Pituitary Adenylate Cyclase Activating Peptides) and galanin allows a new perception of the control and physiology of neuronal operation. We need to advance our knowledge by studying the structure of their receptors ligand binding site, coupling … More sites with effecter mechanisms, phosphorylation, desensitization, receptors coupled to G-protein or ionic channel.The purpose of this study was to examine the role of neuropeptide receptor and its antagonist.The following results were obtained in the present study.1.We have synthesized several peptides related to human secretin precursor. The potency of synthetic peptides was compared in both rats and dogs by determining volume flow of the pancreas.Big secretin (secretin-41) was about 1/3 of the potency of porcine secretin-27. Secretin-41 was also used as immunogen to produce anti-big secretin serum to use as a tool for determining brain secretin (Chey, Mochizuki, Yanaihara).2.We gave tested various PACAP fragments in an attempt to find selective PACAP antagonists. Results showed that both PACAP (5-38) and PACAP (10-38) act as potent antagonists on the receptor-binding, increase of [Ca^<2+>] i and VIP release stimulated by PACAP-38. Both antagonists specifically recognized PACAP receptor (Rosselin, Christophe, Laburthe, Yanaihara).3.On the other hand, PACAP (1-15) was found to antagonize partially PACAP-evoked chloride secretion in isolated guinea-pig distal colon, and PACAP (1-15) did not block the guinea pig VIP-evoked response (Kuwahara).4.[D-Trp^8] galanin (1-15) ol was shown to act as a potent agonist on the specific galanin receptor. The present observation suggests that [D-Trp^8] galanin (1-15) ol may be a key compound to develop a novel galanin antagonist.5.We have examined the effect of extracts of Chinese herb on CCK receptor. Among the extracts examined, lower molecular weight fractions of Saiko extracts were shown to bind the CCK-B receptor. The results showed that Saiko extracts may contain CCK agonist or antagonist (Gardner, Brown, Wei, Yanaihara).The present demonstration showed clearly the importance synthetic peptide fragments to investigate the role of neuropeptide receptor and its antagonists. Less