グアニリンの分子構造、細胞学、生理学とその臨床応用

鸟苷酸的分子结构、细胞学、生理学及其临床应用

基本信息

批准号：
06044104
负责人：
HAYAKAWA Tetsuo
金额：
$ 7.74万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for international Scientific Research
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1996
项目状态：
已结题

项目摘要

Guanylin, isolated from rat small intestine, is a 15 amino acid residue peptide structurally related to the heat-stable enterotoxin (STa) of E.coli. In order to understand its function in health and disease states, we have synthesized guanylin and its precursor related peptides and tried to determine their structure and bindings to their receptors and to identify its producing cells and their tharget organs. Nuclear magnetic resonance spectroscopy revealed that guanylin with disulfids positions 4-12 and 7-15 exists as a mixture of two stable conformations with compact spiral structures. Its isomer with disulfides positions 4-15 and 7-12 showed a single conformation.Immunohistochemical studies in human and rat intestine using antiserum against proguanylin 1-15 indicated that proguanylin-like immunoreactivities were present in the intestinal endocrine cells which were also positive somatostatin but negative to serotonin, suggesting proguanyline may be cosecreted with somatostatin. Progua … More nyline positive cells were abundant in the pyrolic antrum and duodenum. Very few cells were observed in the colon. Both guanylin and STa displaced the binding of ^<125>I-labelled guanylin to crude membrane preparations of rat small intestine in a dose dependent manner with Kd values around 10^<-6> M.The disulfide isomer, on the other hand, bound poorly to the membrane preparations. Most of ^<125>I-guanylin was incorporated into the kidney following the intravenous injection in anesthetized rats. It bound to the luminal surface of proximal tubules. In the collecting ducts, ^<125>I-guanylin appeared to be excreted via chief cells. Guanylin decreased the cell height and increased the luminal space of the inner medullary collecting ducts, suggesting that guanylin has a diuretic action in the collecting ducts. In the small intestine guanylin stimulated mucus secretion from goblet cells in crypts but not in the villi. It appears that guanylin control both intestinal and renal fluid secretion as both paracrine and endocrine hormones. Less

鸟苷素是从大鼠小肠中分离出来的一种 15 个氨基酸残基的肽，其结构与大肠杆菌的热稳定性肠毒素 (STa) 相关。为了了解其在健康和疾病状态下的功能，我们合成了鸟苷素及其前体。相关肽并试图确定它们的结构和与其受体的结合，并鉴定其产生细胞及其目标器官。核磁共振波谱显示鸟苷酸具有二硫键位置。 4-12和7-15以两种稳定构象的混合物存在，具有紧凑的螺旋结构，其具有二硫键位置的异构体4-15和7-12显示出单一构象。使用抗鸟苷蛋白1-原的抗血清对人和大鼠肠道进行免疫组织化学研究。 15表明，肠道内分泌细胞中存在鸟苷酸原样免疫反应性，这些细胞也是生长抑素阳性但血清素阴性，提示原鸟苷酸可能与生长抑素共同分泌，在热解窦和十二指肠中观察到很少的细胞，鸟苷酸和 STa 都取代了 125I 标记的鸟苷酸与粗品的结合。大鼠小肠膜制剂以剂量依赖方式，Kd 值约为 10^<-6> M。二硫键异构体，另一方面静脉注射后，大部分 125 I-鸟苷蛋白与膜制剂结合不良，在集合管中，它与近端肾小管的管腔表面结合。 I-鸟苷蛋白似乎通过主细胞分泌，降低了细胞高度并增加了内髓集合管的管腔空间，表明鸟苷蛋白。在小肠中，鸟苷酸刺激隐窝中杯状细胞的粘液分泌，但在绒毛中则不然。鸟苷酸似乎作为旁分泌激素和内分泌激素控制肠道和肾液的分泌。