Transcytosis, the vesicular transport of macromolecules from one side of a cell to the other, is a strategy used by multicellular organisms to selectively move material between two environments without altering the unique compositions of those environments. In this review, we summarize our knowledge of the different cell types using transcytosis in vivo, the variety of cargo moved, and the diverse pathways for delivering that cargo. We evaluate in vitro models that are currently being used to study transcytosis. Caveolae-mediated transcytosis by endothelial cells that line the microvasculature and carry circulating plasma proteins to the interstitium is explained in more detail, as is clathrin-mediated transcytosis of IgA by epithelial cells of the digestive tract. The molecular basis of vesicle traffic is discussed, with emphasis on the gaps and uncertainties in our understanding of the molecules and mechanisms that regulate transcytosis. In our view there is still much to be learned about this fundamental process.

Transcytosis: Crossing Cellular Barriers

The physiological effects of glucagon-like peptide-1 (GLP-1) are of immense interest because of the potential clinical relevance of this peptide. Produced in intestinal L-cells through posttranslational processing of the proglucagon gene, GLP-1 is released from the gut in response to nutrient ingestion. Peripherally, GLP-1 is known to affect gut motility, inhibit gastric acid secretion, and inhibit glucagon secretion. In the central nervous system, GLP-1 induces satiety, leading to reduced weight gain. In the pancreas, GLP-1 is now known to induce expansion of insulin-secreting beta-cell mass, in addition to its most well-characterized effect: the augmentation of glucose-stimulated insulin secretion. GLP-1 is believed to enhance insulin secretion through mechanisms involving the regulation of ion channels (including ATP-sensitive K(+) channels, voltage-dependent Ca(2+) channels, voltage-dependent K(+) channels, and nonselective cation channels) and by the regulation of intracellular energy homeostasis and exocytosis. The present article will focus principally on the mechanisms proposed to underlie the glucose dependence of GLP-1's insulinotropic effect.

https://diabetes.diabetesjournals.org/content/diabetes/51/suppl_3/S434.full.pdf

The multiple actions of GLP-1 on the process of glucose-stimulated insulin secretion.

Secretory granules are specialized intracellular organelles that serve as a storage pool for selected secretory products. The exocytosis of secretory granules is markedly amplified under physiologically stimulated conditions. While granules have been recognized as post-Golgi carriers for almost 40 years, the molecular mechanisms involved in their formation from the trans-Golgi network are only beginning to be defined. This review summarizes and evaluates current information about how secretory proteins are thought to be sorted for the regulated secretory pathway and how these activities are positioned with respect to other post-Golgi sorting events that must occur in parallel. In the first half of the review, the emerging role of immature secretory granules in protein sorting is highlighted. The second half of the review summarizes what is known about the composition of granule membranes. The numerous similarities and relatively limited differences identified between granule membranes and other vesicular carriers that convey products to and from the plasmalemma, serve as a basis for examining how granule membrane composition might be established and how its unique functions interface with general post-Golgi membrane traffic. Studies of granule formation in vitro offer additional new insights, but also important challenges for future efforts to understand how regulated secretory pathways are constructed and maintained.

Sorting and storage during secretory granule biogenesis: looking backward and looking forward.

The release of insulin from pancreatic islets requires negative regulation to ensure low levels of insulin release under resting conditions, as well as positive regulation to facilitate robust responsiveness to conditions of elevated fuel or glucose The first phase of release involves the plasma-membrane fusion of a small pool of granules, termed the readily releasable pool; these granules are already at the membrane under basal conditions, and discharge their cargo in response to nutrient and also non-nutrient secretagogues By contrast, second-phase secretion is evoked exclusively by nutrients, and involves the mobilization of intracellular granules to t-SNARE sites at the plasma membrane to enable the distal docking and fusion steps of insulin exocytosis Nearly 40 years ago, the actin cytoskeleton was first recognized as a key mediator of biphasic insulin release, and was originally presumed to act as a barrier to block granule docking at the cell periphery More recently, however, the discovery of cycling GTPases that are involved in F-actin reorganization in the islet β-cell, combined with the availability of reagents that are more specific and tools with which to study the mechanisms that underlie granule movement, have contributed greatly to our understanding of the role of the cytoskeleton in regulating biphasic insulin secretion Herein, we provide historical perspective and review recent progress that has been made towards integrating cytoskeletal reorganization and cycling of small Rho-, Rab- and Ras-family GTPases into our current models of stimulus-secretion coupling and second-phase insulin release

/pdf/mechanisms-of-biphasic-insulin-granule-exocytosis-roles-of-qcrq27mtve.pdf

Mechanisms of biphasic insulin-granule exocytosis – roles of the cytoskeleton, small GTPases and SNARE proteins

Secretion of the peptide hormone insulin from pancreatic beta cells constitutes an important step in the regulation of body homeostasis. Insulin is stored in large dense core vesicles and released by exocytosis, a multistage process involving transport of vesicles to the plasma membrane, their docking, priming and finally their fusion with the plasma membrane. Some of the protein components necessary for this process have been identified in beta cells. The export of potent and potentially harmful substances has to be tightly controlled. The secretory response in pancreatic beta cells requires the concerted action of nutrients together with enteric hormones and neurotransmitters acting on G-protein coupled receptors. It is well established that glucose and other metabolizable nutrients depolarize the beta-cell membrane and the ensuing Ca2+ influx through voltage-dependent channels constitutes a main stimulus for insulin exocytosis. Theoretical considerations and recent observations suggest in addition an organizing role for the Ca2+ channel similar to neurotransmission. A second regulatory control on exocytosis is exerted by monomeric and heterotrimeric G-proteins. The monomeric GTPase Rab3A controls insulin secretion through cycling between a guanosine triphosphate liganded vesicle-bound form and a guanosine diphosphate liganded, cytosolic form. The effect of neurohormones is transduced by the heterotrimeric GTPases. Whereas pertussis-toxin sensitive alpha-subunits exert direct inhibition at the level of exocytosis, the Gbeta gamma-subunits are required for stimulation. It is possible that these GTPases exert immediate regulation, while protein kinases and phosphatases may modulate long-term adaptation at the exocytotic machinery itself. The molecular nature of their activators and effectors still await identification. Insights into the progression of the exocytotic vesicle from docking to fusion and how these processes are precisely regulated by proteins and second messengers may provide the basis for new therapeutic principles.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1046/j.1432-1327.1999.00043.x

Molecular mechanisms and regulation of insulin exocytosis as a paradigm of endocrine secretion

Syntaxins are cytoplasmically oriented integral membrane soluble NEM-sensitive factor receptors (SNAREs; soluble NEM-sensitive factor attachment protein receptors) thought to serve as targets for t...

/pdf/distinct-cellular-locations-of-the-syntaxin-family-of-54z6pth1x7.pdf

Distinct cellular locations of the syntaxin family of proteins in rat pancreatic acinar cells.

The vesicle-associated membrane protein family of proteins in rat pancreatic and parotid acinar cells.

The role of SNAP-25 in exocytosis in the rat pancreatic acinar cell

Pancreatic beta cells and cell lines were used in the present study to test the hypothesis that the molecular mechanisms controlling exocytosis from neuronal cells may be used by the beta cell to regulate insulin secretion. Using specific antisera raised against an array of synaptic proteins (SNAREs) implicated in the control of synaptic vesicle fusion and exocytosis, we have identified the expression of several SNAREs in the islet beta cell lines, beta TC6-f7 and HIT-T15, as well as in pancreatic islets. The v-SNARE vesicle-associated membrane protein (VAMP)-2 but not VAMP-1 immunoreactive proteins were detected in beta TC6-f7 and HIT-T15 cells and pancreatic islets. In these islet-derived cell lines, this 18-kDa protein comigrated with rat brain synaptic vesicle VAMP-2, which was cleaved by Tetanus toxin (TeTx). Immunofluorescence confocal microscopy and electron microscopy localized the VAMP-2 to the cytoplasmic side of insulin containing secretory granule membrane. In streptolysin O permeabilized HIT-T15 cells, TeTx inhibited Ca2+-evoked insulin release by 83 +/- 4.3%, which correlated well to the cleavage of VAMP-2. The beta cell lines were also shown to express a second vesicle (v)-SNARE, cellubrevin. The proposed neuronal target (t)-membrane SNAREs, SNAP-25, and syntaxin isoforms 1-4 were also detected by Western blotting. The beta cell 25-kDa SNAP-25 protein and syntaxin isoforms 1-3 were specifically cleaved by botulinum A and C toxins, respectively, as observed with the brain isoforms. These potential t-SNARES were localized by immunofluorescence microscopy primarily to the plasma membrane in beta cell lines as well as in islet beta cells. To determine the specific identity of the immunoreactive syntaxin-2 and -3 isoforms and to explore the possibility that these beta cells express the putative Ca2+-sensing molecule synaptotagmin III, RT-PCR was performed on the beta cell lines. These studies confirmed that betaTC6-F7 cells express syntaxin-2 isoforms, 2 and 2', but not 2'' and express syntaxin-3. They further demonstrate the expression of synaptotagmin III. DNA sequence analysis revealed that rat and mouse beta cell syntaxins 2, 2' and synaptotagmin III are highly conserved at the nucleotide and predicted amino acid levels (95-98%). The presence of VAMP-2, nSec/Munc-18, SNAP-25 and syntaxin family of proteins, along with synaptotagmin III in the islet cells and in beta cell lines provide evidence that neurons and beta cells share similar molecular mechanisms for Ca2+-regulated exocytosis. The inhibition of Ca2+-evoked insulin secretion by the proteolytic cleavage of HIT-T15 cell VAMP-2 supports the hypothesis that these proteins play an integral role in the control of insulin exocytosis.

Characterization of SNARE protein expression in beta cell lines and pancreatic islets.

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Distinct cellular locations of the syntaxin family of proteins in rat pancreatic acinar cells.

The vesicle-associated membrane protein family of proteins in rat pancreatic and parotid acinar cells.

The role of SNAP-25 in exocytosis in the rat pancreatic acinar cell

Characterization of SNARE protein expression in beta cell lines and pancreatic islets.