グアニリンの分子構造、細胞学、生理学とその臨床応用

鸟苷素是从大鼠小肠中分离得到的一种15个氨基酸残基的多肽，结构上与大肠杆菌的耐热性肠毒素(StA)有关。为了了解鸟苷素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多肽，并试图确定它们的结构和与其受体的结合，并鉴定其产生细胞和靶器官。核磁共振波谱分析表明，鸟苷二硫键位置为4-12和7-15，是两种稳定构象的混合物，具有紧密的螺旋结构。其4-15和7-12位二硫键的异构体呈单一构象。用Proguanylin 1-15抗血清在人和大鼠肠道进行的免疫组织化学研究表明，Proguanylin样免疫反应存在于肠内分泌细胞中，生长抑素阳性而5-羟色胺阴性，提示Proguanyine可能与生长抑素共分泌。Progua…在胃窦和十二指肠有较多的Nyline阳性细胞。结肠内可见极少的细胞。鸟苷素和StA均以剂量依赖的方式取代标记鸟苷素与大鼠小肠粗膜制剂的结合，Kd值在10~(-6)&gt；M左右，而二硫异构体与膜制剂的结合较差。麻醉大鼠静脉注射鸟苷素后，大部分已进入肾脏。它与近端小管的管腔表面结合。在集合管中，I-鸟苷可通过主细胞分泌。鸟苷素降低内髓集合管的细胞高度，增加管腔间隙，提示鸟苷素对集合管具有利尿作用。在小肠中，鸟苷素刺激隐窝中的杯状细胞分泌粘液，但不刺激绒毛中的粘液分泌。鸟苷素似乎既作为旁分泌激素又作为内分泌激素控制肠道和肾液的分泌。较少

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