DEVELOPMENT OF GASTRIC HCL SECRETION

胃盐酸分泌的发展

• 批准号: 3238599
• 负责人: JOHN G FORTE
• 金额: $ 21.39万
• 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/3238599
• 关键词: adenosinetriphosphatase; apical membrane; cell differentiation; cytoplasm; glucocorticoids; glycoproteins; growth /development; hydrochloric acid; hydrogen; laboratory mouse; laboratory rabbit; membrane activity; membrane reconstitution /synthesis; membrane transport proteins; oligosaccharides; posttranslational modifications; potassium; protein sequence; secretion; 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。主泵酶 负责HCl分泌的已被确定为H，K-ATPase。二 H，K-ATPase的非常重要的活性是其基础 参与胃分泌；三磷酸腺苷产生的H+交换转运 对于K+；以及刺激调节的H，K-ATPase的回收 胞质膜域延伸至顶端细胞表面。这项研究将 研究胃泵酶及其辅助性成分 它在分泌周期中的作用和调节。最新发现 提示H，K-ATPase是一种稳定为α/β的复合酶 功能膜中的原构体，类似于密切相关的Na， K-ATPase。我们认为H，K-ATPase全酶由94 KDA催化α亚基和糖蛋白β亚基。对于一个专业来说 本研究项目的具体目的是为了刻画 提出H，K-ATPase的β-亚基，并建立其功能 作用于泵酶的运转和周转。因此，我们 建议建立拟议的空间和时间协调 推定的β亚基中的α和β亚基，包括初级 氨基酸序列和二级结构将用于 与其他已知泵蛋白的功能和理论比较，以及 详细的低聚糖结构作为表面组织和 可能保护壁细胞表面。 另一个主要项目将利用新生兔胃模型来 壁细胞的发生和成熟及H，K-ATPase泵的研究 系统，以及控制它们个体发育的信号。具体目标是 旨在确定含有胃的细胞膜的起源 泵酶、组成多肽的组成和合成速率 (例如，建议的阿尔法和贝塔亚基)，以及翻译后 在成熟过程中发生的变化。加速的本质 糖皮质激素促进胃发育的定义将在 关于糖皮质激素受体的位置和反应， 激活细胞和诱导蛋白质合成，并直接或 糖皮质激素对成分转录的间接作用 H，K-ATPase的多肽。