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Physiological study of Cl^- channels associated with gastric proton pump and liver multidrug efflux pump

胃质子泵和肝脏多药外排泵相关Cl^-通道的生理研究

基本信息

批准号：
05454139
负责人：
TAKEGUCHI Noriaki
金额：
$ 3.46万
依托单位：
TOYAMA MEDICAL AND PHARMACEUTICAL 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：
1993
资助国家：
日本
起止时间：
1993 至 1994
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05454139/
关键词：
Gastric proton pump multidrug efflux pump Cl^- channel

项目摘要

Gastric proton pump is the terminal target of the stimulus-secretion coupling in the acid secretory mechanism. In 1987, we found that Cl^- channel was the part of the function of this proton pump ; that is, two functions of the Cl^- channel and the proton pump are coexisted in the same molecule. In 1992, Cambridge and Oxford researchers found a similar finding with the multidrug efflux pump.In the first year of this grant, we established the model system in which the function of multidrug efflux pump was visualized and the side effect of cyclosporin in liver transplantation was found to be due to inhibition of the multidrug efflux pump by cyclosporin (Transplantation, 1993). The inhibition of the efflux pump was not found with FK506 at the clinical dose. The conformation of gastric proton pump was differently affected by omeprazole and E3810 which are irreversible inhibitors (J.Biol.Chem., 1993). We also found a new type of Cl^- channel in the gastric acid secreting cell (J.Physiol., 1993).In the second year, we studied the intracellular transport of the pump bound by the inhibitors (Biochem.Phannacol., 1994). The C-terminal topology of this pump in the membrane was studied by raising a monoclonal antibody (Biochem.J., 1994). The molecular structure of gastric proton pump is slightly different from that of the colonic proton pump. We succeeded to raise two monoclonal antibodies ; one binds only to the gastric pump and the other binds to both pumps (J.Biochem., 1994). The intracellular regulatory mechanism of the cytoprotective Cl^- channel was also studied (J.Biol.Chem., 1994). We also prepared cDNAs which encode alpha and beta subunits of gastric proton pump.

胃质子泵是胃酸分泌机制中刺激-分泌偶联的终末靶点。1987年，我们发现Cl^-通道是该质子泵功能的一部分，即Cl^-通道和质子泵两种功能同时存在于同一分子中。1992年，剑桥和牛津大学的研究人员在多药外排泵中发现了类似的发现，在该基金的第一年，我们建立了模型系统，在该系统中，多药外排泵的功能是可视化的，并发现环孢菌素在肝移植中的副作用是由于环孢菌素对多药外排泵的抑制（Transplantation，1993）。在临床剂量下，FK 506未发现外排泵抑制。胃质子泵的构象受到奥美拉唑和E3810的不同影响，奥美拉唑和E3810是不可逆抑制剂（J.Biol.Chem.，1993年）。我们还在胃酸分泌细胞中发现了一种新型的Cl^-通道（J.Physiol.，1993）。在第二年，我们研究了抑制剂所结合的泵的细胞内转运（Biochem.Biennacol.，1994年）。该泵在膜中的C-末端拓扑通过产生单克隆抗体（Biochem.J.，1994年）。胃质子泵的分子结构与结肠质子泵略有不同。我们成功地产生了两种单克隆抗体;一种仅与胃泵结合，另一种与两种泵结合（J.Biochem.，1994年）。还研究了细胞保护性Cl^-通道的细胞内调节机制（J.Biol.Chem.，1994年）。我们还制备了编码胃质子泵α和β亚基的cDNA。