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Molecular Biological Studies on the Action Mechanisms of Motilin and its Receptor

胃动素及其受体作用机制的分子生物学研究

基本信息

批准号：
02454227
负责人：
ITOH Zen
金额：
$ 4.22万
依托单位：
Gunma University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1990
资助国家：
日本
起止时间：
1990 至 1991
项目状态：
已结题

项目摘要

Motilin is a polypeptide consisting of 22 amino acid residues and was originally isolated from the duodenal mucosa of hogs The major functions of motilin appear to be the acceleration of gastric emptying and the apparent initiation of the interdigestive migrating contractions (IMC). Rhythmic oscillations of circulating motilin levels, with peaks occuring every 90-120 min, correlate well with the appearance of phase Ill motor activity in the gastrointestinal tract. Furthermore, intravenous infusion of motilin in -concious dogs and humans during the interdigestive period initiated IMCs in the anteroduodenal region. In vivo studies demonstrate that cholinergic blockade with atropine abolished the stimulating effect of motilin in fundic and antral pouches of stomach and motilin increases IMC in denervated stomach but not denervated jejunum in dogs. Thus, both humoral and neural mechanisms have been postulated to be responsible for the action of motilin. However, the mechanism responsible f … More or the action of motilin on gastrointestinal motility is unclear at the cellular and molecular levels. We postulated the existence of motilin receptors on rabbit antral and duodenal smooth muscle tissues and attempted the demonstration of direct binding of ^<125>l-motilin to its receptors. The specific binding of ^<125>l-motilin to duodenal muscle slice was initially demonstrated by both its direct binding and displacement of ^<125>l-motilin by a variety of non-labeled analogues including erythromycin derivatives. However, the specific binding of ^<125>l-motilin to isolated smooth muscle membranes was not confirmed by some unknown reasons. We are currently trying to show that motilin may act through presynaptic nerve endings that may release acetylcholine or other neurotransmitters. At the same time we have prepared highly radioactive motilin ligands with substitution of methionin for leucine at position 13 and with addition of tyrosine at less bioactive sites of the motilin sequence in order to maintain highly specific binding activity. At present we are continuing the binding study of ^<125>l-motilin to rabbit antral and duodenal smooth muscle cell membranes. Less

胃动素是由22个氨基酸残基组成的多肽，最初从猪的十二指肠粘膜中分离得到。胃动素的主要功能是加速胃排空和启动消化间期移行性收缩（IMC）。循环胃动素水平的节律性振荡，每90-120分钟出现一次峰值，与胃肠道III期运动活动的出现密切相关。此外，在消化间期静脉输注胃动素可启动前十二指肠区的IMC。在体研究表明，胆碱能阻断阿托品取消胃底和胃窦袋胃动素的刺激作用，胃动素增加IMC在去神经胃，但不去神经空肠在狗。因此，体液和神经机制已被假定为负责胃动素的行动。然而，负责f的机制 ...更多信息或者胃动素对胃肠运动的作用在细胞和分子水平上尚不清楚。我们假定胃动素受体存在于兔胃窦和十二指肠平滑肌组织上，并试图证明胃<125>动素与其受体的直接结合。胃<125>动素与十二指肠肌片的特异性结合最初通过其直接结合和<125>被包括红霉素衍生物在内的各种非标记类似物置换来证明。然而，<125>由于一些未知的原因，胃动素与离体平滑肌膜的特异性结合并未得到证实。我们目前正试图证明胃动素可能通过突触前神经末梢释放乙酰胆碱或其他神经递质发挥作用。同时，我们制备了高放射性胃动素配体，其在位置13处用甲硫氨酸取代亮氨酸，并在胃动素序列的生物活性较低的位点处添加酪氨酸，以保持高特异性结合活性。目前，我们正在继续进行胃<125>动素与兔胃窦和十二指肠平滑肌细胞膜结合的研究。少