DEVELOPMENT OF GASTRIC HCL SECRETION

胃盐酸分泌的发展

• 批准号: 3238598
• 负责人: JOHN G FORTE
• 金额: $ 20.73万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3238598
• 关键词: adenosinetriphosphatase; apical membrane; cell differentiation; cytoplasm; glucocorticoids; glycoproteins; growth /development; hydrochloric acid; laboratory mouse; laboratory rabbit; membrane activity; membrane channels; membrane reconstitution /synthesis; oligosaccharides; posttranslational modifications; protein sequence; secretion; sodium potassium exchanging ATPase; stomach; swine

The general goal of this research is to advance our understanding of the cellular and molecular basis of HCl secretion. The principal pump enzyme responsible for HCl secretion has been identified as the H, K-ATPase. Two very important activities of the H,K-ATPase are fundamental to its participation in gastric secretion; ATP-generated exchange transport of H+ for K+; and stimulation-regulated recycling of H,K-ATPase from a cytoplasmic membrane domain to the apical cell surface. This research will study the gastric pump enzyme, and the accessory elements that contribute to its function and regulation in the secretory cycle. Recent discoveries suggest that the H,K-ATPase is a complex enzyme stabilized as an alpha/beta protomer in the functional membrane, analogous to the closely related Na, K-ATPase. Wee propose that the H,K-ATPase holoenzyme is made up of a 94 kDa catalytic alpha-subunit and a glycoprotein beta-subunit. For one major project of this research specific aims are directed at characterizing the proposed beta-subunit for the H,K-ATPase, and establishing its functional role in the operation and turnover of the pump enzyme. Accordingly, we propose to establish the spatial and temporal concordance of the proposed alpha- and beta-subunits in the putative beta-subunit, including primary amino acid sequence and secondary structure that will be used for functional and theoretical comparisons with other known pump proteins, and detailed oligosaccharide structure as a basis for surface organization and possible protection of parietal cell surfaces. The other major project will exploit the neonatal rabbit stomach model to study genesis and maturation of parietal cells, the H,K-ATPase pumping system, and the signals that control their ontogeny. Specific aims are directed at establishing the origin of cell membrane containing the gastric pump enzyme, the composition and synthetic rates for component peptides (e.g., proposed alpha- and beta-subunits), and post-translational modifications effected during maturation. The nature of accelerated gastric development promoted by glucocorticoid hormones will be defined in terms of location and responsiveness of glucocorticoid receptors, activation of cells and induction of protein synthesis, and the direct or indirect action of glucocorticoid on transcription of the component peptides of the H,K-ATPase.

这项研究的总体目标是增进我们对 HCl 分泌的细胞和分子基础。 主要泵酶 负责 HCl 分泌的物质已被确定为 H,K-ATP 酶。 二 H,K-ATP酶的非常重要的活性是其基础 参与胃分泌； ATP 产生的 H+ 交换运输 对于K+；和刺激调节 H,K-ATP 酶的回收 细胞质膜结构域至顶端细胞表面。 这项研究将 研究胃泵酶以及有助于胃泵酶的辅助元素 其在分泌周期中的功能和调节。 最近的发现 表明 H,K-ATP 酶是一种稳定为 α/β 的复杂酶 功能膜中的原聚体，类似于密切相关的Na， K-ATP酶。 Wee 提出 H,K-ATPase 全酶是由 94 kDa 催化 α 亚基和糖蛋白 β 亚基。 对于一个专业 本研究项目的具体目标是表征 提出了 H,K-ATP 酶的 β 亚基，并建立了其功能 在泵酶的运行和周转中发挥作用。 据此，我们 提议建立拟议的空间和时间一致性 假定的 β 亚基中的 α 和 β 亚基，包括初级 将用于的氨基酸序列和二级结构 与其他已知泵蛋白的功能和理论比较，以及 详细的寡糖结构作为表面组织的基础 可能保护壁细胞表面。 另一个重大项目将利用新生兔胃模型来 研究壁细胞的发生和成熟、H,K-ATP酶泵送 系统，以及控制其个体发育的信号。 具体目标是 旨在建立含有胃的细胞膜的起源 泵酶、成分肽的组成和合成率 （例如，建议的 α 和 β 亚基）和翻译后 成熟过程中发生的改变。 加速的本质 糖皮质激素促进的胃发育将被定义为 糖皮质激素受体的位置和反应性， 激活细胞和诱导蛋白质合成，以及直接或 糖皮质激素对该成分转录的间接作用 H,K-ATP酶的肽。