Parotid Secretory Granules: Crossroads of Secretory Pathways and Protein Storage

Abstract

Saliva plays an important role in digestion, host defense, and lubrication. The parotid gland contributes a variety of secretory proteins-including amylase, proline-rich proteins, and parotid secretory protein (PSP)-to these functions. The regulated secretion of salivary proteins ensures the availability of the correct mix of salivary proteins when needed. In addition, the major salivary glands are targets for gene therapy protocols aimed at targeting therapeutic proteins either to the oral cavity or to circulation. To be successful, such protocols must be based on a solid understanding of protein trafficking in salivary gland cells. In this paper, model systems available to study the secretion of salivary proteins are reviewed. Parotid secretory proteins are stored in large dense-core secretory granules that undergo stimulated secretion in response to extracellular stimulation. Secretory proteins that are not stored in large secretory granules are secreted by either the minor regulated secretory pathway, constitutive secretory pathways (apical or basolateral), or the constitutive-like secretory pathway. It is proposed that the maturing secretory granules act as a distribution center for secretory proteins in salivary acinar cells. Protein distribution or sorting is thought to involve their selective retention during secretory granule maturation. Unlike regulated secretory proteins in other cell types, salivary proteins do not exhibit calcium-induced aggregation. Instead, sulfated proteoglycans play a role in the storage of secretory proteins in parotid acinar cells. This work suggests that unique sorting and retention mechanisms are responsible for the distribution of secretory proteins to different secretory pathways from the maturing secretory granules in parotid acinar cells.

Role for the actomyosin complex in regulated exocytosis revealed by intravital microscopy

“…In SGs, proteins are secreted at the APM primarily through the regulated exocytosis of large SCGs (7). As a model to image the dynamics of these vesicles, we used transgenic mice ubiquitously expressing a soluble form of the green fluorescent protein (GFP) (28).…”

“…in vivo imaging | cytoskeleton R egulated exocytosis is a key cellular process in which molecules destined for secretion are packaged into vesicles that constitutively bud from the trans-Golgi network and, upon receiving the appropriate stimuli, fuse with the plasma membrane (PM), releasing their content into the extracellular space (1)(2)(3)(4). One of the experimental models that has been extensively used to study the regulated exocytosis is the acinar cells of the salivary glands (SGs) in which the large SCGs, upon stimulation of the appropriate G protein-coupled receptors, fuse with the apical plasma membrane (APM), where they release their contents into a network of canaliculi and ducts (5)(6)(7). In SGs, three fundamental questions need to be addressed: (i) what stimulus triggers exocytosis of the large SCGs?…”

“…Moreover, using isolated acinar preparations, several groups have reported a wide spectrum of contradictory findings. For example, in vivo and ex vivo studies suggest that in parotid and submandibular SGs, the release of secretory proteins is primarily controlled by the β-adrenergic receptor (7,8). However, other studies showed that the muscarinic receptor can also stimulate exocytosis and play a synergistic role in the β-adrenergic-mediated release of the SCGs (9-11).…”

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

“…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]. At present no universal sorting signals for secretory proteins have been identified in any cell type.…”

“…Several distinct protein secretion pathways have been identified in salivary gland cells, within the general constitutive and RSP categories, including both major and minor regulated pathways, apical and basolateral constitutive pathways, and a constitutive-like pathway [9,15]. These lead to specific sorting routes for transgenic secretory proteins in an endocrine and exocrine manner [16].…”