PEPTIDE HORMONE SORTING TO THE SECRETORY/STORAGE GRANULE

所有的细胞都会合成分泌蛋白质，但特殊的多肽- 分泌神经内分泌细胞已经发展出一条额外的途径 胞吐作用强烈的颗粒中多肽激素的储存 受特定生理刺激调节的。由于存储颗粒 富含不同于构成和分泌的蛋白质 那些集中在溶酶体中的专业分泌细胞必须 通过过程在内部区分这些不同类别的蛋白质 它们统称为分子分类。中国的脊椎动物门 一般人，尤其是人类，已经将多肽激素的分泌调整为 对抗代谢平衡紊乱的一条主要防线；因此 似乎内分泌细胞中多肽的分子分类， 再加上触发分泌动作的信号，代表着 内分泌动态平衡所基于的精确调节。在一个 一系列人类和动物疾病，包括某些已知的基因 上述类别的分子分类中的突变、变化 分子与各种异常有关，从微小的表型 缺陷是缺乏生命力的有机体。很明显，为了 为了阐明这些分类缺陷的潜在基础，我们必须有 对分拣过程中涉及的分子机制的应用知识 流程。然而，到目前为止，关于 相互矛盾的假说被用来解释多肽激素是如何 通常靶向并集中在分泌颗粒中。简而言之， 这些观点可以分为“条目排序”假设，在这个假设中 蛋白质是在高尔基复合体中预先选择的，以进入存储 颗粒，而不是“按保留排序”假说 含量蛋白质以可溶混合物的形式进入形成颗粒；然后非 储存的蛋白质被选择性地(和非选择性地)移除，而 受调节的分泌蛋白通过缩合成一个 不溶的核心。尽管盛行的科学观点认为 被调节的分泌蛋白被分类以进入存储颗粒 途径，这项赠款申请采取的观点，并打算 进一步检验按保留排序的假说。对…的回顾 背景信息以及几个重要的初步调查结果 为创新实验奠定基础并确立其可行性 其结果可能会导致我们大幅修改我们的思维方式 关于肽荷尔蒙是如何分类和储存的。

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 processes that are collectively known as molecular sorting. The vertebrate phylum in general, and man in particular, have adapted peptide-hormone secretion as a major line of defense against disturbances in metabolic balance; thus it appears that the molecular sorting of polypeptides in endocrine cells, coupled with the signalling that triggers secretagogue action, represent the precision tuning upon which endocrine homeostasis is based. In an array of human and animal diseases including certain known genetic mutations, alterations in molecular sorting of the above classes of molecules are associated with abnormalities ranging from subtle phenotypic defects to lack of viability of the organism. It is evident that in order to elucidate the underlying basis for these sorting defects, we must have a working knowledge of the molecular mechanisms involved in sorting processes. However, up to now, there has been great controversy over conflicting hypotheses created to explain how peptide hormones are normally targeted and concentrated in secretory granules. In a nutshell, these views can be divided into a "sorting for entry" hypothesis in which proteins are pre-selected in the Golgi complex for entry into storage granules, versus a "sorting by retention" hypothesis in which unsorted content proteins enter forming granules as a soluble mixture; then non- stored proteins are selectively (and non-selectively) removed while regulated secretory proteins are retained by condensation into an insoluble core. Although the prevailing scientific view has been that regulated secretory proteins are sorted for entry into the storage granule pathway, this grant application takes the point of view of, and intends to further examine, the sorting-by-retention hypothesis. A review of background information as well as several important preliminary findings lay the groundwork and establish the feasibility of novel experiments whose outcome could cause us to revise substantially the way we think about how peptide hormones are sorted and stored.