グアニリンの分子構造、細胞学、生理学とその臨床応用

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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