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Cloning of new endothelin B receptor and its physiological significance

新内皮素B受体的克隆及其生理意义

基本信息

批准号：
06454157
负责人：
KIMURA Sadao
金额：
$ 4.86万
依托单位：
Chiba 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：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06454157/
关键词：
Endothelin Endothelin receptor Hirschsprung disease エンドセリン受容体血管平滑筋

项目摘要

1.Analysis of endothelin receptor subtypesTo study endothelin (ET) receptor subtypes which mediate smooth muscle contraction of the rabbit and human saphenous veins, effects of some ET receptor agonists and antagonists were examined. Our results indicated pharmacological heterogeneity (ET_<A1>, ET_<A2> ; ET_<B1>, ET_<B2>) of both ET_A and ET_B recetor-mediated contractions. The currently available data, as well as those obtained in the present study, clearly indicate pharmacological heterogeneity of responses to endothelins, but they are not yet sufficient to provide conclusive evidence for endothelin receptor nomenclature. However, additional pharmacological data using ET_B-deficient mice clearly indicated that these pharmacologically heterogenous responses of ET_B receptor are completely lost, suggesting that ET_<B1> and ET_<B2> receptors are derived from a single ET_B gene.2.Mutation analysis of endothelin B receptor in Hirschsprung diseaseHirschsprung's disease (HSCR) is characterized by the absence of autonomic ganglion cells in the terminal bowel and is a relatively common cause of intestinal obstruction in the newborn. Recently, ET_B gene has been shown as a susceptibility gene for HSCR by the production of aganglionic colon in mice with a null mutation of this gene and by demonstrating a missense mutation in a large inbred kindred with a high incidence of HSCR (Mennonite pedigree). However, no further mutations have been demonstrated in other clinical cases. We analyzed alterations of the ET_B gene in 31 isolated patients of HSCR.Three novel mutations were detected : A to T, T to C and C to A transitions at nucleotide 311,325 and 1170, respectively. These mutations resulted in Asn to Ile, Cys to Arg and Ser to Arg, predicted to produce a non-functional ET_B receptor. These observations indicate that dysfunction or loss of function of ET_B receptor may be involved in the aetiology of some isolated patients with HSCR.

1.内皮素受体亚型的分析为研究内皮素（ET）受体亚型介导的家兔和人隐静脉平滑肌收缩，检测了一些ET受体激动剂和拮抗剂的作用。结果表明，ET_A和ET_B受体介导的收缩反应具有药理学异质性（ET_<A1>，ET_<A2>; ET_<B1>，ET_<B2>）。目前可用的数据，以及在本研究中获得的数据，清楚地表明对内皮素的反应的药理学异质性，但它们还不足以为内皮素受体命名提供确凿的证据。然而，ET_B缺陷小鼠的药理学数据清楚地表明，ET_B受体的这些异质性反应完全丧失，这表明ET_B<B1>和ET_B<B2>受体来源于单一的ET_B基因。其特征在于末端肠中缺乏自主神经节细胞，并且是新生儿肠梗阻的相对常见的原因。近年来，ET_B基因无效突变小鼠结肠无神经节细胞的形成和门诺家系（Mennonite pedigree）中高发病率的一个大的近交系中的错义突变证实了ET_B基因是HSCR的易感基因。然而，在其他临床病例中没有进一步的突变。我们分析了31例HSCR患者ET_B基因的变异，发现3个新的突变：311、325和1170位核苷酸的A → T、T → C和C → A转换。这些突变导致Asn突变为Ile、Cys突变为Arg、Ser突变为Arg，预测产生无功能的ET_B受体。这些观察结果表明，ET_B受体功能障碍或功能丧失可能与某些孤立的HSCR患者的病因有关。