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

Abstract

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.

Elucidating the Role of Disulfide Bond on Amyloid Formation and Fibril Reversibility of Somatostatin-14

“…However, it also required that the granules dock onto the plasma membrane and release their contents in a controlled manner upon receiving the external signal (2,38,79). Therefore, the peptide/protein hormone amyloids inside the granules require stability for it to be suitably stored in addition to being reversible, thus allowing it to release monomers to the extracellular space.…”

Utilizing endocrine secretory pathways in salivary glands for systemic gene therapeutics

“…Resident ER proteins are actively identified, through a KDEL sequence, and retained or transported back to the ER when dislocated (Nilsson and Warren, 1994). Other nascent proteins are subsequently collected in the transitional ER-Golgi intermediate compartment (ERGIC area) and transported to the Golgi complex, i.e., the cis, medial, trans, and trans-Golgi network (TGN; Dannies, 1999;Allan et al, 2002). Two models have been proposed for transport through the Golgi complex (Dannies, 1999).…”

“…Other nascent proteins are subsequently collected in the transitional ER-Golgi intermediate compartment (ERGIC area) and transported to the Golgi complex, i.e., the cis, medial, trans, and trans-Golgi network (TGN; Dannies, 1999;Allan et al, 2002). Two models have been proposed for transport through the Golgi complex (Dannies, 1999). According to the first model, vesicles shuttle the secretory proteins from one compartment to the next, while in the second, the processing enzymes are transported between compartments.…”

“…Regulated secretion is triggered by an extracellular stimulus and leads to a massive release of the stored protein. Amino acid and other structural signals are thought to identify regulated pathway proteins and affect their sorting behavior in the TGN, where the immature secretory granules form and bud (Dannies, 1999;Gorr et al, 2001;Loh et al, 2002, see below).…”

Sorting of growth hormone–erythropoietin fusion proteins in rat salivary glands

“…In the first, proteins are secreted as fast as they are synthesized, in a constitutive, non-directional manner and independent from changes in second messenger levels. In the second pathway, the regulated secretory pathway (RSP), proteins destined for secretion are sorted and stored in high concentrations in secretory granules where they await an external secretory stimulus [3][4][5]. RSP proteins require an amino acid-based sorting signal and evidence supports both the "sortingfor-entry" and "sorting-by-retention" hypotheses for these proteins [6][7][8][9][10].…”