Secretory vesicle

FIGURE 25.38 Lipoprotein components are synthesized predominantly in the ER of liver cells. Following assembly of lipoprotein particles red dots) in the ER and processing in the Golgi, lipoproteins are packaged in secretory vesicles for export from the cell (via exocy-tosis) and released into the circulatory system. 

Like all neuropeptides, NT is synthesized as part of a larger precursor that also contains neuromedin N (NN), a 6 amino acid neurotensin-like peptide (Table 1). Pro-NT/NN is processed in the regulated secretory pathway of neuroendocrine cells by prohormone convertases PCI, PC2 and PC5-A that belong to a larger family of proprotein convertases. Due to differential cleavage specificity and tissue distribution of the convertases, pro-NT/NN processing gives rise to approximately a 1 1 and a 5 1 ratio of NT over NN content in the brain and gut, respectively. The peptides are stored in secretory vesicles and released from neuroendocrine cells in a Ca2+-dependent manner. NT and NN actions are terminated by desensitization of the... 

Transport supplies nerve cells with neurotransmitter, which is used to replenish secretory vesicles, thus uptake occurs on the cell surface and on the secretory vesicle. 

Neurotransmitter Transporters. Figure 3 Dopamine turnover at a presynaptic nerve terminal, (a) Dopamine is produced by tyrosine hydroxylase (TH). When secretory vesicles are filled, they join the releasable pool of vesicles at the presynaptic membrane. Upon exocytosis, the diffusion of released dopamine is limited by reuptake via DAT. (b) If DAT is inactive, dopamine spreads in the cerebrospinal fluid but cannot accumulate in secretory vesicles. This results in a compensatory increase of dopamine hydroxylase activity and a higher extracellular dopamine level mice with inactive DAT are hyperactive. 

In the trans Golgi compartment the peptide is sorted via secretory vesicles into a regulated pathway. In contrast to vesicles of the constitutive pathway, vesicles of the regulated pathway are stored in the cytoplasm until their stimulated release. Membrane depolarisation as well as a wide range of substances such as intracellular mediators, neuropeptides, neurotransmitters, classical hormones, cytokines, growth factors, ions and nutrients induce somatostatin secretion. General inhibitors of somatostatin release are opiates, GABA, leptin and TGF- 3. 

Chromaffin granules, platelet dense core vesicles, and synaptic vesicles accumulate ATP. ATP uptake has been demonstrated using chromaffin granules and synaptic vesicles and the process appears to depend on A(.lh+. It has generally been assumed that ATP is costored only with monoamines and acetylcholine, as an anion to balance to cationic charge of those transmitters. However, the extent of ATP storage and release by different neuronal populations remains unknown, and the proteins responsible for ATP uptake by secretory vesicles have not been identified. 

JV Greiner, KR Kenyon, AS Henriquez, DR Korb, TA Weidman, MR Allansmith. (1980). Mucus secretory vesicles in conjunctival epithelial cells of wearers of contact lenses. Arch Ophthalmol 98 1843-1846. 

Schuldiner, S., Steiner-Mordoch, S., Yelin, R., Wall, S.C., and Rudnick, G., Amphetamine derivatives interact with both plasma membrane and secretory vesicle biogenic amine transporters, Mol. Pharmacol. 44(6), 1227-1231, 1993. 

Secretory cells, including neurons, also possess a specialized regulated secretory pathway. Vesicles in this pathway have soluble proteins, peptides or neurotransmitters stored and concentrated within secretory vesicles. At that point, these vesicles are actively transported to a site for extracellular delivery in response to a specific extracellular signal. Exocytosis through regulated secretion accomplishes different functions, including the... 

At least two classes of regulated secretion can be defined [54]. The standard regulated secretion pathway is common to all secretory cells (i.e. adrenal chromaffin cells, pancreatic beta cells, etc.) and works on a time scale of minutes or even longer in terms of both secretory response to a stimulus and reuptake of membranes after secretion. The second, much faster, neuron-specific form of regulated secretion is release of neurotransmitters at the synapse. Release of neurotransmitters may occur within fractions of a second after a stimulus and reuptake is on the order of seconds. Indeed, synaptic vesicles may be recycled and ready for another round of neurotransmitter release within 1-2 minutes [64]. These two classes of regulated secretion will be discussed separately after a consideration of secretory vesicle biogenesis. 

Secretory vesicle biogenesis requires completion of a characteristic sequence of steps before they are competent for secretion. Secretory cells typically invest a substantial fraction of their biosynthetic capacity for generation of secretory vesicles and their secreted products. Neurons devote a particularly high fraction of their biosynthetic activity to the synthesis and assembly of secretory organelles. In secretory cells, the bulk of newly synthesized... 

As secretory vesicles mature, many secretory polypeptides undergo post-translational modifications. Many hormones and neuropeptides as well as hydrolytic enzymes are synthesized as inactive polypeptide precursors that need to undergo proteolysis to become active. This maturation process usually starts in the TGN and continues in the secretory vesicles, but may be completed in the extracellular space soon after exocytosis takes place in some cases. The maturation process for neuropeptides is described in Chapter 18. 

One characteristic of regulated exocytosis is the ability to store secretory vesicles in a reserve pool for utilization upon stimulation. In the presynaptic terminal, this principle is expanded to define multiple pools of synaptic vesicles a ready releasable pool, a recycled synaptic vesicle pool and a larger reserve pool. This reserve pool assures that neurotransmitter is available for release in response to even the highest physiological demands. Neurons can fire so many times per minute because synaptic vesicles from the ready releasable pool at a given synapse undergo exocytosis in response to a single action potential. 

As noted above, synaptic vesicles are not typically generated at the level of the TGN. Instead, they are assembled from endocytosed material retrieved from the synaptic plasma membrane. Synaptic vesicle and plasma membrane lipids and proteins are synthesized in the endoplasmic reticulum and modified in the Golgi apparatus, where they are then packaged in secretory vesicles. These synaptic precursors are delivered to the plasma membrane from the cell body by the constitutive secretory pathway. Synaptic vesicle proteins must be retrieved by clathrin-mediated synaptic vesicle endocytosis, a variant of RME with some neuron-specific components. Once the vesicle sheds its clathrin coat, the uncoated vesicle fuses with a... 

Cysteine string protein (CSP) Cytochrome b561 Peripheral membrane protein that is paimitoylated on >10 cysteines. May have a role in Ca2+ sensitivity of exocytosis. Electron-transport protein required for intravesicular monooxygenases in subsets of secretory vesicles. Required for dopamine- -hydroxylase and peptide amidase activity. 

Breckenridge, L. J. and Aimers, W. Currents through the fusion pore that forms during exocytosis of a secretory vesicle. Nature 328 814-817,1987. 

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