DEVELOPMENT OF GASTRIC HCL SECRETION

这项研究的总体目标是促进我们对 HCl分泌的细胞和分子基础。 主泵酶 已经确定负责HCl分泌的是H，K-ATP酶。 两 H，K-ATP酶的非常重要的活性是其活性的基础。 参与胃液分泌; ATP产生的H+交换转运 和刺激调节的H，K-ATP酶的再循环， 细胞质膜结构域的顶端细胞表面。 这项研究将 研究胃泵酶，以及有助于 它在分泌周期中的功能和调节。 最近的发现 表明H，K-ATP酶是一种稳定的α/β复合酶， 功能膜中的原聚体，类似于密切相关的Na， K-ATP酶 我们认为H，K-ATP酶全酶由94个氨基酸组成， kDa催化α-亚基和糖蛋白β-亚基。 一个主要的 本研究项目的具体目标是针对表征 提出了H，K-ATP酶的β亚基，并建立了其功能 作用于酶泵的运转和周转。 因此我们 建议建立拟议的空间和时间一致性， 假定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。 另一个主要项目将利用新生兔胃模型， 研究壁细胞的发生和成熟，H，K-ATPase泵 系统，以及控制其个体发育的信号。 具体的目标是 旨在建立含胃粘膜的细胞膜的起源， 泵酶、组分肽的组成和合成速率 (e.g.,提出的α-和β-亚基），和翻译后 在成熟过程中发生的变化。 加速的性质 糖皮质激素促进的胃发育将在 就糖皮质激素受体的位置和反应性而言， 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。

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.