Protein Hormone Storage in Secretory Granules: Mechanisms for Concentration and Sorting1

Recent findings in cell biology have demonstrated there are several kinds of active sorting from the trans-Golgi network in all cells. The presence of several sorting pathways, using more than one sorting signal, in neuroendocrine cells means that mutations that direct a hormone to a constitutive pathway instead of a regulated one may not simply be interpreted as a signal for sorting to a regulated pathway. The use of three-dimensional electron microscopy of lactotrophs and the possibility that the trans-Golgi network is consumed during sorting has suggested a major role for hormone aggregation, not only as a sorting mechanism, but also as a mechanism for granule formation, in that other transport vesicles may bud from the trans-Golgi network, leaving the aggregated protein as the dense core granule. If aggregation plays such a role, it is unclear how it works in cases where the prohormone must be processed one or more times; does a porous aggregate or colloid form? Obtaining information about the kinds of aggregates that occur in cells is difficult, because at this time there is not a definitive way of knowing whether an aggregate that occurs in solution also occurs in cells. Although secretory granule proteins tend to aggregate relatively easily in solution, the separate treatment of different secretory granule proteins in the same cell make it unlikely that aggregation is a purely passive process, but suggests that the process of aggregation of each hormone is actively controlled in cells. Even if the ability to aggregate accounts for most of the sorting of cargo-secretory granule proteins into granules, other sorting must still occur to get correct membrane proteins necessary for transport and exocytosis into secretory granule membranes. Possible recognition sites for these secretory granule membrane proteins include the cargo itself in an aggregated form, membrane lipids in some unrecognized way, or the proteins and factors that specifically control aggregation of the cargo.