Exocytosis, secretory protein

Secretory glycoproteins are known to move from the ER to the Golgi complex where their carbohydrate side chains are trimmed and further modified (see Palade, 1975 Tartakoff, 1980 Farquhar and Palade, 1981). In most secretory cells the proteins are then concentrated into condensing vacuoles which store the secretory proteins until they are discharged by exocytosis through a fusion reaction between the vacuolar membrane and the plasma membrane. In other secretory cells, like plasma cells, proteins are condnuously secreted and they appear to leave the Golgi complex within vesicles without being concentrated before exocytosis. 

Fig. 1. Exocytosis of proteins by the constitutive and regulated secretory pathways.

Fig. 1. Synthesis and exocytosis of secretory proteins see text for details. The ribosomes attached to the RER are shown as filled-in circles whereas the open circles in the lumen of the ER, vesicles and Golgi complex represent secretory protein molecules.

Figure 5 Proteomics reveals functional secretory vesicle protein systems for neuropeptide biosynthesis, storage, and secretion. Chromaffin secretory vesicles (also known as chromaffin granules) were isolated and subjected to proteomic analyses of proteins in the soluble and membrane components of the vesicles. Protein systems in secretory vesicle function consisted of those for 1) production of hormones, neurotransmitters, and neuromodulatory factors, 2) generating selected internal vesicular conditions for reducing condition, acidic pH conditions maintained by ATPases, and chaperones for protein folding, and 3) vesicular trafficking mechanisms to allow the mobilization of secretory vesicles for exocytosis, which uses proteins for nucleotide-binding, calcium regulation, and vesicle exocytosis. These protein systems are coordinated to allow the secretory vesicle to synthesize and release neuropeptides for cell-cell communication in the control of neuroendocrine functions.

Fig. 15.14. Fate of proteins synthesized on the RER. Proteins synthesized on ribosomes attached to the ER travel in vesicles to the cis face of the Golgi complex. After the membranes fuse, the proteins enter the Golgi complex. Structural features of the proteins determine their fate. Some remain in the Golgi complex, and some return to the RER. Others bud from the trans face of the Golgi complex in vesicles. These vesicles can become lyso-somes or secretory vesicles, depending on their contents. Secretory proteins are released from the cell when secretory vesicles fuse with the cell membrane (exocytosis). Proteins with hydrophobic regions embedded in the membrane of secretory vesicles become cell membrane proteins. See Chapter 10 for descriptions of the endoplasmic reticulum, Golgi complex, lysosomes, and the cell membrane, and also for an explanation of the process of exocytosis.

Protein trafficking is the transport of proteins to their correct subcellular compartments or to the extracellular space ( secretory pathway ). Endo- and exocytosis describe vesicle budding and fusion at the plasma membrane and are by most authors not included in the term protein trafficking. Protein quality control comprize all cellular mechanisms, monitoring protein folding and detecting aberrant forms. 

Protein/peptide hormones are derived from amino acids. These hormones are preformed and stored for future use in membrane-bound secretory granules. When needed, they are released by exocytosis. Protein/peptide hormones are water soluble, circulate in the blood predominantly in an unbound form, and thus tend to have short half-lives. Because these hormones are unable to cross the cell membranes of their target tissues, they bind to receptors... 

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... 

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. 

P cells of the pancreatic islets in combination with atoms of zinc, but when required to regulate blood glucose concentration, the prohormone is cleaved and functional insulin is released into the circulation along with the C-peptide. This example of post-translational processing is mediated by peptidases which are contained in the vesicles along with the proinsulin. The fusion of the secretory vesicles with the cell membrane and activation of the peptidase prior to exocytosis of the insulin are prompted by an influx of calcium ions into the P-cell in response to the appropriate stimulus. Similarly, catecholamines are synthesized and held within the cell by attachment to proteins called chromogranins. 

From the Golgi apparatus, the proteins are transported by vesicles to various targets in the cells—e.g., to lysosomes (4), the plasma membrane (6), and secretory vesicles (5) that release their contents into the extracellular space by fusion with the plasma membrane (exocytosis see p. 228). Protein transport can either proceed continuously (constitutive), or it can be regulated by chemical signals. The decision regarding which pathway a protein... 

Exocytosis is a term referring to processes that allow cells to expel substances (e.g., hormones or neurotransmitters) quickly and in large quantities. Using a complex protein machinery, secretory vesicles fuse completely or partially with the plasma membrane and release their contents. Exocytosis is usually regulated by chemical or electrical signals. As an example, the mechanism by which neurotransmitters are released from synapses (see p. 348) is shown here, although only the most important proteins are indicated. 

Most neurotransmitter release occurs by exocytosis of secretory vesicles, which involves the fusion of the secretory vesicles (synaptic vesicles and LDCVs) with the plasma membrane. All intracellular membrane fusion (except for mitochondrial fusion) is thought to operate by the same fundamental mechanism that involves a core machinery composed of four classes of proteins SNARE-proteins, SM-proteins (for... 

The SNAREs involved in the fusion of synaptic vesicles and of secretory granules in neuroendocrine cells, referred to as neuronal SNAREs, have been intensely studied and serve as a paradigm for all SNAREs. They include syntaxin 1A and SNAP-25 at the presynaptic membrane and synaptobrevin 2 (also referred to as VAMP 2) at the vesicle membrane. Their importance for synaptic neurotransmission is documented by the fact that the block in neurotransmitter release caused by botulinum and tetanus neurotoxins is due to proteolysis of the neuronal SNAREs (Schiavo et al. 2000). Genetic deletion of these SNAREs confirmed their essential role in the last steps of neurotransmitter release. Intriguingly, analysis of chromaffin cells from KO mice lacking synaptobrevin or SNAP-25 showed that these proteins can be at least partially substituted by SNAP-23 and cellubrevin, respectively (Sorensen et al. 2003 Borisovska et al. 2005), i.e., the corresponding SNAREs involved in constitutive exocytosis. 

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