PEPTIDE HORMONE SORTING TO THE SECRETORY/STORAGE GRANU

所有的细胞都分泌蛋白质，但特殊的多肽- 分泌神经内分泌细胞已经开发了一种额外的途径， 肽激素在胞吐作用剧烈的颗粒中的储存 由特定的生理刺激调节。 由于存储颗粒是 富含不同于组成型分泌的蛋白质， 那些集中在溶酶体，专业分泌细胞必须 通过复合物在内部区分这些不同种类的蛋白质 这一过程统称为分子分选和靶向。 这样的 这个过程具有重要的生物学意义，因为这个基本机制， 结合内分泌细胞中的刺激-分泌偶联， 作为抵抗代谢紊乱的主要防线 体内平衡 在一系列人类/动物疾病中， 上述分子类别的分子分选与以下有关： 从细微的表型缺陷到缺乏 生存能力 该补助金继续侧重于获得工作知识 分泌细胞中蛋白质分选的分子机制 通路 在过去四年中取得了很大进展;然而， 关于两种不同的模式仍然存在相当大的争议， 它们并不相互排斥，它们被用来解释肽 激素和其他腔蛋白被递送到，并储存在， 分泌颗粒这两种观点中的第一种观点是“排序”， 进入”模型，其中蛋白质的子集是预先选择在 trans-Golgi网络进入存储颗粒，而其他蛋白质 被有效地排除在外。 第二个模型被称为 “通过保留进行分选”，其中进入储存颗粒不 需要参与不溶性蛋白质复合物或受体 形成颗粒膜。 在这种情况下，进入形成 颗粒可能不是受调节的分泌蛋白所独有的;然而， 成熟过程中的高阶分子间相互作用（缩合） 颗粒促进蛋白质保留在颗粒隔室内。 与此同时，退出路径有效地移除某些选定的 通过受体介导的囊泡出芽从成熟颗粒中提取蛋白质， 伴随着一部分分泌蛋白的被动去除 其具有低效的保持性能。 本补助金的目标是 应用程序继续探索这种排序的各个方面， 保留假说 重要的初步调查结果提出 这建立了新的实验的可行性基础3 具体目标。

All cells secrete proteins constitutively, but specialized polypeptide- secreting neuroendocrine cells have developed an additional pathway of storage of peptide hormones in granules whose exocytosis is acutely regulated by specific physiologic stimuli. Since storage granules are enriched in proteins different from those secreted constitutively and those concentrated in lysosomes, professional secretory cells must internally distinguish these different classes of proteins by a complex process known collectively as molecular sorting and targeting. Such a process has great biological significance, because this basic mechanism, in conjunction with stimulus-secretion coupling in endocrine cells, serves as a primary line of defense against disturbances in metabolic homeostasis. In an array of human/animal diseases, alterations in molecular sorting of the above classes of molecules are associated with abnormalities ranging from subtle phenotypic defects to lack of viability. This grant continues to focus on gaining a working knowledge of molecular mechanism's involved in protein sorting in the secretory pathway. Much progress has been made in the past 4 years; however, considerable controversy remains over two different models, which are not mutually exclusive, that have been created to explain how peptide hormones and other luminal proteins are delivered to, and stored within, secretory granules. The first of these two views is a "sorting for entry" model in which a subset of proteins are pre-selected in the trans-Golgi network for entry into storage granules while other proteins are efficiently excluded from entry. The second model is termed "sorting by retention" in which entry into storage granules does not require participation in an insoluble protein complex nor to a receptor in the forming granule membrane. In this view, entry into forming granules may not be exclusive to regulated secretory proteins; however, higher-order intermolecular interactions (condensation) within maturing granules facilitates protein retention within the granule compartment. At the same time, an exit route efficiently removes certain selected proteins from maturing granules by receptor-mediated vesicle budding, accompanied by the passive removal of a fraction of secretory proteins that have inefficient retention properties. The goals of this grant application continue to be to explore aspects of this sorting-by- retention hypothesis. Important preliminary findings are presented which establish the feasibility of novel experiments underlying 3 Specific Aims.