To explore the molecular basis of ligand binding and receptor activation of human motlin receptor

探讨人胃动蛋白受体配体结合和受体激活的分子基础

• 批准号: 18590683
• 负责人: MATSUURA Bunzo
• 金额: $ 2.41万
• 依托单位: Ehime University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590683/
• 关键词: Motilin receptor; Mntilin; Erythromycin; Diabetes mellitus

Background and Aims: Motilin is an important endogenous regulator of gastrointestinal motor function, mediated by the class I G protein-coupled motilin receptor Motilin and erythromycin, two chemically distinct full agonists of the motilin receptor, are known to bind to distinct regions of this receptor, based on previous systematic mutagenesis of extracellular regions that dissociated the effects on these two agents. While there has been dysmotility of GI tract in patients with diabetes mellitus, roles of this receptor is not yet clear. In the current work, we have examined the predicted intracellular loop domains of this receptor for effects on motilin- and erythromycin-stimulated activity, and explored the distribution of this receptor along the GI tract in diabetic patients. Methods: We have studied sequential deletions of residues within the predicted first, second, and third intracellular loop domains of the motilin receptor and have utilized alanine, phenylalanine, and histidine … More replacement fur each residue within functionally important segments. Post-mortem and surgical human tissue specimens with no hemorrhage, necrosis, or tumor were obtained from lower esophagus, stomach, duodenum, jejunum, ileum, colon, and rectum in subjects with and without diabetes mellitus. We analyzed expression of mRNA and immunoreactivity of motilin and GHS receptors. Results: Tyr66, Arg136, and Val299 were critical on motilin and erythromycin biological activity. These data suggested that action by different chemical classes of agonists likely yield a common activation state of the cytosolic face of this receptor that is responsible for interaction with its G protein. In diabetic patients, motilin receptor was expressed 10 to 100 times more in the muscle layer than in mucosal layer, similar to non-diabetic subjects. These data suggested that motilin agonists such as peptide motilide and non-peptidyl erythromycin and ghrelin agonists may be useful drugs for dysmotility of GI tract in diabetic patients. Less

背景和目标：胃动素是胃肠道运动功能的重要内源性调节剂，由I类G蛋白偶联胃动素受体介导。胃动素和红霉素是胃动素受体的两种化学上不同的完全激动剂，已知它们与该受体的不同区域结合，这是基于先前对细胞外区域的系统性诱变，所述系统性诱变分离了对这两种药剂的作用。虽然糖尿病患者存在胃肠道运动障碍，但该受体的作用尚不清楚。在目前的工作中，我们已经研究了预测的细胞内环域的这种受体的胃动素和红霉素刺激的活动的影响，并探讨了这种受体的分布沿着胃肠道在糖尿病患者。研究方法：我们已经研究了在胃动素受体的预测的第一、第二和第三胞内环结构域内的残基的连续缺失，并利用丙氨酸、苯丙氨酸和组氨酸 ...更多信息 在功能上重要的片段内替换每个残基。从患有和不患有糖尿病的受试者的食管下段、胃、十二指肠、空肠、回肠、结肠和直肠中获得无出血、坏死或肿瘤的尸检和手术人体组织标本。分析胃动素和GHS受体的mRNA表达和免疫反应性。结果：Tyr66、Arg136和Val299是影响胃动素和红霉素生物活性的关键基因。这些数据表明，不同化学类别的激动剂的作用可能产生该受体的胞质面的共同激活状态，该受体负责与其G蛋白的相互作用。在糖尿病患者中，胃动素受体在肌肉层中的表达是粘膜层的10至100倍，与非糖尿病受试者相似。这些数据表明，胃动素激动剂，如肽胃动素和非肽基红霉素和胃饥饿素激动剂可能是有用的药物治疗糖尿病患者的胃肠道动力障碍。少

项目成果

Tissue distribution of the motilin and ghrelin receptor along the human gastrointestinal tract in diabetic patients

糖尿病患者胃动素和生长素释放肽受体沿人体胃肠道的组织分布

• 发表时间: 2007
• 作者: Matsuura;B;Takeshita;E;Ueda;T;Furukawa;S;Dong;M;Miller;LJ;Murakami;H;Matsui;H;Onji;M
• 通讯作者: M

Tissue distribution of the motilin and ghrelin receptor along the human gastrointestinal tract

胃动素和生长素释放肽受体沿人体胃肠道的组织分布

• 发表时间: 2006
• 作者: Takeshita;E;Matsuura;B;Dong;M;Miller;LJ;Matsui;H;Hiasa;Y;Onji;M
• 通讯作者: M

Identification of peptide-ligand binding domains of the growth hormone secretagogue receptor, compared to the motilin receptor

与胃动素受体相比，生长激素促分泌素受体的肽-配体结合域的鉴定

• 发表时间: 2006
• 作者: Matsuura;B;Ueda;T;Dong;M;Miller;IA;Utsunomiya;S;Matsui;H;Hiasa;Y;Onji;M
• 通讯作者: M

Diabetes mellitus reduces the therapeutic effectiveness of interferon-alpha 2b plus ribavirin therapy in patients with chronic hepatitis C

糖尿病降低了干扰素-α2b加利巴韦林治疗慢性丙型肝炎患者的治疗效果

• 发表时间: 2007
• 期刊: Hepatol Res 37
• 作者: Konishi;I;Horiike;N;Hiasa;Y;Tokumoto;Y;Mashiba;T;Michitaka;K;Miyake;Y;Nonaka;S;Joukou;K;Matsuura;B;Onji;M
• 通讯作者: M

Molecular characterization and distribution of motilin family receptors in the human gastrointestinal tract

• DOI: 10.1007/s00535-005-1739-0
• 发表时间: 2006-03
• 期刊: Journal of Gastroenterology
• 影响因子: 6.3
• 作者: E. Takeshita;B. Matsuura;M. Dong;L. Miller;H. Matsui;M. Onji