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Nội dung chính Show- Many Proteins and Lipids Seem to Be Carried Automatically from the Golgi Apparatus to the Cell SurfaceSecretory Vesicles Bud from the Trans Golgi NetworkProteins Are Often Proteolytically Processed During the Formation of Secretory VesiclesSecretory Vesicles Wait Near the Plasma Membrane Until Signaled to Release Their ContentsRegulated Exocytosis Can Be a Localized Response of the Plasma Membrane and Its Underlying CytoplasmSecretory Vesicle Membrane Components Are Quickly Removed from the Plasma MembranePolarized Cells Direct Proteins from the Trans Golgi Network to the Appropriate Domain of the Plasma MembraneCytoplasmic Sorting Signals Guide Membrane Proteins Selectively to the Basolateral Plasma MembraneLipid Rafts May Mediate Sorting of Glycosphingolipids and GPI-anchored Proteins to the Apical Plasma MembraneSynaptic Vesicles Can Form Directly from Endocytic Vesicles
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Having considered the cell's internal digestive system and the various types of incoming membrane traffic that converge on lysosomes, we now return to the Golgi apparatus and examine the secretory pathways that lead out to the cell exterior. Transport vesicles destined for the plasma membrane normally leave the trans Golgi network in a steady stream. The membrane proteins and the lipids in these vesicles provide new components for the cell's plasma membrane, while the soluble proteins inside the vesicles are secreted to the extracellular space. The fusion of the vesicles with the plasma membrane is called . In this way, for example, cells produce and secrete most of the proteoglycans and glycoproteins of the extracellular matrix, which is discussed in Chapter 19.
All cells require this . Specialized secretory cells, however, have a second secretory pathway in which soluble proteins and other substances are initially stored in secretory vesicles for later release. This is the regulated secretory pathway, found mainly in cells specialized for secreting products rapidly on demand—such as hormones, neurotransmitters, or digestive enzymes (). In this section we consider the role of the Golgi apparatus in both of these secretory pathways and compare the two mechanisms of secretion.
Figure 13-54The constitutive and regulated secretory pathways. The two pathways diverge in the trans Golgi network. The constitutive secretory pathway operates in all cells. Many soluble proteins are continually secreted from the cell by this pathway, which also (more...)
Many Proteins and Lipids Seem to Be Carried Automatically from the Golgi Apparatus to the Cell Surface
In a cell capable of regulated secretion, least three classes of proteins must be separated before they leave the trans Golgi network—those destined for lysosomes (via late endosomes), those destined for secretory vesicles, and those destined for immediate delivery to the cell surface. We have already noted that proteins destined for lysosomes are tagged for packaging into specific departing vesicles (by mannose-6-phosphate for lysosomal hydrolases), and analogous signals are thought to direct secretory proteins into secretory vesicles. Most other proteins are transported directly to the cell surface by the nonselective constitutive secretory pathway. Because entry into this pathway does not require a particular signal, it is also called the (). Thus, in an unpolarized cell such as a white blood cell or a fibroblast, it seems that any protein in the lumen of the Golgi apparatus is automatically carried by the constitutive pathway to the cell surface unless it is either specifically returned to the ER, retained as a resident protein in the Golgi apparatus itself, or selected for the pathways that lead to regulated secretion or to lysosomes. In polarized cells, where different products have to be delivered to different domains of the cell surface, we shall see that the options are more complex.
Figure 13-55The three best-understood pathways of protein sorting in the trans Golgi network. (1) Proteins with the mannose 6-phosphate (M6P) marker are diverted to lysosomes (via late endosomes) in clathrin-coated transport vesicles (see Figure 13-37). (2) Proteins (more...)
Secretory Vesicles Bud from the Trans Golgi Network
Cells that are specialized for secreting some of their products rapidly on demand concentrate and store these products in (often called secretory granules or dense-core vesicles because they have dense cores when viewed in the electron microscope). Secretory vesicles form from the trans Golgi network, and they release their contents to the cell exterior by exocytosis in response to extracellular signals. The secreted product can be either a small molecule (such as histamine) or a protein (such as a hormone or digestive enzyme).
Proteins destined for secretory vesicles (called secretory proteins) are packaged into appropriate vesicles in the trans Golgi network by a mechanism that is believed to involve the selective aggregation of the secretory proteins. Clumps of aggregated, electron-dense material can be detected by electron microscopy in the lumen of the trans Golgi network. The signal that directs secretory proteins into such aggregates is not known, but it is thought to be composed of signal patches that are common to proteins of this class. When a gene encoding a secretory protein is transferred to a secretory cell that normally does not make the protein, the foreign protein is appropriately packaged into secretory vesicles. This observation shows that although the proteins that an individual cell expresses and packages in secretory vesicles differ, they all contain common sorting signals, which function properly even when the proteins are expressed in cells that do not normally make them.
It is unclear how the aggregates of secretory proteins are segregated into secretory vesicles. Secretory vesicles have unique proteins in their membrane, some of which might serve as receptors for aggregated protein in the trans Golgi network. The aggregates are much too big, however, for each molecule of the secreted protein to be bound by its own cargo receptor, as proposed for transport of the lysosomal enzymes. The uptake of the aggregates into secretory vesicles may therefore more closely resemble the uptake of particles by phagocytosis the cell surface, where the plasma membrane zippers up around large structures.
Initially, most of the membrane of the secretory vesicles that leave the trans Golgi network is only loosely wrapped around the clusters of aggregated secretory proteins. Morphologically, these resemble dilated trans Golgi cisternae that have pinched off from the Golgi stack. As the vesicles mature, their contents become concentrated (), probably as the result of both the continuous retrieval of membrane that is recycled back to late endosomes and the progressive acidification of the vesicle lumen that results from the progressive concentration of ATP-driven H+ pumps in the vesicle membrane. The degree of concentration of proteins during the formation and maturation of secretory vesicles is small, however, compared with the total 200–400-fold concentration that occurs after they leave the ER. Secretory and membrane proteins become concentrated as they move from the ER through the Golgi apparatus because of an extensive retrograde retrieval process mediated by COPI-coated transport vesicles that exclude them (see ).
Figure 13-56The formation of secretory vesicles. (A) Secretory proteins become segregated and highly concentrated in secretory vesicles by two mechanisms. First, they aggregate in the ionic environment of the trans Golgi network; often the aggregates become more (more...)
Membrane recycling is important for returning Golgi components to the Golgi apparatus, as well as for concentrating the contents of secretory vesicles. The vesicles that mediate this retrieval originate as clathrin-coated buds on the surface of immature secretory vesicles, often being seen even on budding secretory vesicles that have not yet severed from the Golgi stack (see ).
Because the final mature secretory vesicles are so densely filled with contents, the secretory cell can disgorge large amounts of material promptly by exocytosis when triggered to do so ().
Figure 13-57Exocytosis of secretory vesicles. The electron micrograph shows the release of insulin from a secretory vesicle of a pancreatic β-cell. (Courtesy of Lelio Orci, from L. Orci, J.-D. Vassali, and A. Perrelet, Sci. Am. 256:85–94, 1988.)
Proteins Are Often Proteolytically Processed During the Formation of Secretory Vesicles
Condensation is not the only process to which secretory proteins are subject as the secretory vesicles mature. Many polypeptide hormones and neuropeptides, as well as many secreted hydrolytic enzymes, are synthesized as inactive protein precursors from which the active molecules have to be liberated by proteolysis. These cleavages begin in the trans Golgi network, and they continue in the secretory vesicles and sometimes in the extracellular fluid after secretion has occurred. Many secreted polypeptides have, for example, an N-terminal pro-peptide that is cleaved off to yield the mature protein. These proteins are thus synthesized as pre-pro-proteins, the pre-peptide consisting of the ER signal peptide that is cleaved off earlier in the rough ER (see ). In other cases, peptide-signaling molecules are made as polyproteins that contain multiple copies of the same amino acid sequence. In still more complex cases, a variety of peptide-signaling molecules are synthesized as parts of a single polyprotein that acts as a precursor for multiple end-products, which are individually cleaved from the initial polypeptide chain. The same polyprotein may be processed in various ways to produce different peptides in different cell types ().
Figure 13-58Alternative processing pathways for the prohormone proopiomelanocortin. The initial cleavages are made by proteases that cut next to pairs of positively charged amino acids (Lys-Arg, Lys-Lys, Arg-Lys, or Arg-Arg pairs). Trimming reactions then produce (more...)
Why is proteolytic processing so common in the secretory pathway? Some of the peptides produced in this way, such as the enkephalins (five-amino-acid neuropeptides with morphine-like activity), are undoubtedly too short in their mature forms to be co-translationally transported into the ER lumen or to include the necessary signal for packaging into secretory vesicles. In addition, for secreted hydrolytic enzymes—or any other protein whose activity could be harmful inside the cell that makes it—delaying activation of the protein until it reaches a secretory vesicle or until after it has been secreted has a clear advantage: it prevents it from acting prematurely inside the cell in which it is synthesized.
Secretory Vesicles Wait Near the Plasma Membrane Until Signaled to Release Their Contents
Once loaded, a secretory vesicle has to get to the site of secretion, which in some cells is far away from the Golgi apparatus. Nerve cells are the most extreme example. Secretory proteins, such as peptide neurotransmitters (neuropeptides) that are to be released from nerve terminals the end of the axon, are made and packaged into vesicles in the cell body toàn thân, where the ribosomes, ER, and Golgi apparatus are located. They must then travel along the axon to the nerve terminals, which can be a meter or more away. As discussed in Chapter 16, motor proteins propel the vesicles along axonal microtubules, whose uniform orientation guides the vesicles in the proper direction. Microtubules also guide vesicles to the cell surface for constitutive exocytosis.
Whereas vesicles containing materials for constitutive release fuse with the plasma membrane once they arrive there, secretory vesicles in the regulated pathway wait the membrane until the cell receives a signal to secrete and then fuse. The signal is often a chemical messenger, such as a hormone, that binds to receptors on the cell surface. The resulting activation of the receptors generates intracellular signals, often including a transient increase in the concentration of không lấy phí Ca2+ in the cytosol. In nerve terminals, the initial signal for exocytosis is usually an electrical excitation (an action potential) triggered by a chemical transmitter binding to receptors elsewhere on the same cell surface. When the action potential reaches the nerve terminals, it causes an influx of Ca2+ through voltage-gated Ca2+ channels. The binding of Ca2+ ions to specific sensors then triggers the secretory vesicles (called synaptic vesicles) to fuse with the plasma membrane and release their contents to the extracellular space.
The speed of transmitter release indicates that the proteins mediating the fusion reaction do not undergo complex, multistep rearrangements. After vesicles have been docked to the presynaptic plasma membrane, they undergo a priming step, which prepares them for rapid fusion. The SNAREs may be partly paired, but their helices are not fully wound into the final four-helix bundle required for fusion (see ). Other proteins are thought to keep the SNAREs from completing the fusion reaction until the Ca2+ influx releases this brake. At a typical synapse, only few of the docked vesicles seem to be primed and ready for exocytosis. The use of only a few vesicles a time allows each synapse to fire over and over again in quick succession. With each firing, new synaptic vesicles become primed to replace those that have fused and released their contents.
Regulated Exocytosis Can Be a Localized Response of the Plasma Membrane and Its Underlying Cytoplasm
Histamine is a small molecule secreted by mast cells. It is released by the regulated pathway in response to specific ligands that bind to receptors on the mast cell surface. Histamine is responsible for many of the unpleasant symptoms that accompany allergic reactions, such as itching and sneezing. When mast cells are incubated in fluid containing a soluble stimulant, massive exocytosis occurs all over the cell surface (). But if the stimulating ligand is artificially attached to a solid bead so that it can interact only with a localized region of the mast cell surface, exocytosis is now restricted to the region where the cell contacts the bead ().
Figure 13-59Electron micrographs of exocytosis in rat mast cells. (A) An unstimulated mast cell. (B) This cell has been activated to secrete its stored histamine by a soluble extracellular stimulant. Histamine-containing secretory vesicles are dark, while those that (more...)
Figure 13-60Exocytosis as a localized response. This electron micrograph shows a mast cell that has been activated to secrete histamine by a stimulant coupled to a large solid bead. Exocytosis has occurred only in the region of the cell that is in contact with the (more...)
This experiment shows that individual segments of the plasma membrane can function independently in regulated exocytosis. As a result, the mast cell, unlike a nerve cell, does not respond as a whole when it is triggered; the activation of receptors, the resulting intracellular signals, and the subsequent exocytosis are all localized in the particular region of the cell that has been excited. Such localized exocytosis enables a killer lymphocyte, for example, to deliver the proteins that induce the death of a single infected target cell precisely without endangering normal neighboring cells (see ).
Secretory Vesicle Membrane Components Are Quickly Removed from the Plasma Membrane
When a secretory vesicle fuses with the plasma membrane, its contents are discharged from the cell by exocytosis, and its membrane becomes part of the plasma membrane. Although this should greatly increase the surface area of the plasma membrane, it does so only transiently, because membrane components are removed from the surface by endocytosis almost as fast as they are added by exocytosis, reminiscent of the exocytosis-endocytosis cycle discussed earlier. After their removal from the plasma membrane, the proteins of the secretory vesicle membrane are thought to be shuttled to lysosomes for degradation. The amount of secretory vesicle membrane that is temporarily added to the plasma membrane can be enormous: in a pancreatic acinar cell discharging digestive enzymes for delivery to the gut lumen, about 900 μm2 of vesicle membrane is inserted into the apical plasma membrane (whose area is only 30 μm2) when the cell is stimulated to secrete.
Control of membrane traffic thus has a major role in maintaining the composition of the various membranes of the cell. To maintain each membrane-enclosed compartment in the secretory and endocytotic pathways a constant size, the balance between the forward and retrograde flows of membrane needs to be precisely regulated. For cells to grow, the forward flow needs to be greater than the retrograde flow, so that the membrane can increase in area. For cells to maintain a constant size, the forward and retrograde flows must be equal. We still know very little about the mechanisms that coordinate these flows.
Polarized Cells Direct Proteins from the Trans Golgi Network to the Appropriate Domain of the Plasma Membrane
Most cells in tissues are polarized and have two (and sometimes more) distinct plasma membrane domains to which different types of vesicles must be directed. This raises the general problem of how the delivery of membrane from the Golgi apparatus is organized so as to maintain the differences between one cell-surface domain and another. A typical epithelial cell has an apical domain, which faces the lumen and often has specialized features such as cilia or a brush border of microvilli; it also has a basolateral domain, which covers the rest of the cell. The two domains are separated by a ring of tight junctions (see ), which prevent proteins and lipids (in the outer leaflet of the lipid bilayer) from diffusing between the two domains, so that the compositions of the two domains are different.
A nerve cell is another example of a polarized cell. The plasma membrane of its axon and nerve terminals is specialized for signaling to other cells, whereas the plasma membrane of its cell body toàn thân and dendrites is specialized to receive signals from other nerve cells. The two domains have distinct protein compositions. Studies of protein traffic in nerve cells in culture suggest that, with regard to vesicular transport from the trans Golgi network to the cell surface, the plasma membrane of the nerve cell body toàn thân and dendrites resembles the basolateral membrane of a polarized epithelial cell, while the plasma membrane of the axon and its nerve terminals resembles the apical membrane of such a cell (). Thus, some proteins that are targeted to a specific domain in the epithelial cell are also found to be targeted to the corresponding domain in the nerve cell.
Figure 13-61A comparison of two types of polarized cells. In terms of the mechanisms used to direct proteins to them, the plasma membrane of the nerve cell body toàn thân and dendrites resembles the basolateral plasma membrane domain of a polarized epithelial cell, whereas (more...)
Cytoplasmic Sorting Signals Guide Membrane Proteins Selectively to the Basolateral Plasma Membrane
In principle, differences between plasma membrane domains need not depend on the targeted delivery of the appropriate membrane components. Instead, membrane components could be delivered to all regions of the cell surface indiscriminately, but then be selectively stabilized in some locations and selectively eliminated in others. Although this strategy of random delivery followed by selective retention or removal seems to be used in certain cases, deliveries are often specifically directed to the appropriate membrane domain. Epithelial cells, for example, frequently secrete one set of products—such as digestive enzymes or mucus in cells lining the gut— their apical surface, and another set of products—such as components of the basal lamina— their basolateral surface. Thus, cells must have ways of directing vesicles carrying different cargoes to different plasma membrane domains.
By examining polarized epithelial cells in culture, it has been found that proteins from the ER destined for different domains travel together until they reach the trans Golgi network. Here they are separated and dispatched in secretory or transport vesicles to the appropriate plasma membrane domain ().
Figure 13-62Two ways of sorting plasma membrane proteins in a polarized epithelial cell. Newly synthesized proteins can reach their proper plasma membrane domain by either (A) a direct pathway or (B) an indirect pathway. In the indirect pathway, a protein is retrieved (more...)
Membrane proteins destined for delivery to the basolateral membrane contain sorting signals in their cytoplasmic tail. Two such signals are known, one containing a characteristic conserved tyrosine and the other two adjacent leucines. When present in an appropriate structural context, these amino acids are recognized by coat proteins that package them into appropriate transport vesicles in the trans Golgi network. The same basolateral signals that are recognized in the trans Golgi network also function in endosomes to redirect the proteins back to the basolateral plasma membrane after they have been endocytosed.
Lipid Rafts May Mediate Sorting of Glycosphingolipids and GPI-anchored Proteins to the Apical Plasma Membrane
The apical plasma membrane of most cells is greatly enriched in glycosphingolipids, which help protect this exposed surface from damage—by the digestive enzymes and low pH in such sites as the stomach or the lumen of the gut, for example. Plasma membrane proteins that are linked to the lipid bilayer by a glycosylphosphatidylinositol (GPI) anchor are also found exclusively in the apical plasma membrane. If recombinant DNA techniques are used to attach a GPI anchor to a protein that would normally be delivered to the basolateral surface, the protein is now delivered to the apical surface instead.
GPI-anchored proteins are thought to be directed to the apical membrane because they associate with the glycosphingolipids in that form in the membrane of the trans Golgi network. As discussed in Chapter 10, lipid rafts form in the trans Golgi network and plasma membrane when glycosphingolipids and cholesterol self-associate into microaggregates (see ). Membrane proteins with unusually long transmembrane domains also accumulate in the rafts. In addition, the rafts preferentially contain GPI-anchored proteins and some carbohydrate-binding proteins (lectins) that may help stabilize the assemblies ().
Figure 13-63Model of lipid rafts in the trans Golgi network. Glycosphingolipids and cholesterol are thought to form rafts in the lipid bilayer. Membrane proteins with long enough membrane-spanning segments preferentially partition into the lipid rafts and thus become (more...)
Having selected a unique set of cargo molecules, the rafts then bud from the trans Golgi network into transport vesicles destined for the apical plasma membrane.
Synaptic Vesicles Can Form Directly from Endocytic Vesicles
Nerve cells (and some endocrine cells) contain two types of secretory vesicles. As for all secretory cells, these cells package proteins and peptides in dense-cored secretory vesicles in the standard way for release by the regulated secretory pathway. In addition, however, they make use of another specialized class of tiny (~50-nm diameter) secretory vesicles, which are called and are generated in a different way. In nerve cells, these vesicles store small neurotransmitter molecules, such as acetylcholine, glutamate, glycine, and γ-aminobutyric acid (GABA), that mediate rapid signaling from cell to cell chemical synapses. As discussed earlier, the vesicles are triggered to release their contents within a fraction of a millisecond when an action potential arrives a nerve terminal. Some neurons fire more than 1000 times per second, releasing neurotransmitters each time. This rapid release is possible because some of the vesicles are docked and primed for fusion, which will occur only when an action potential causes an influx of Ca2+ into the terminal.
Only a small proportion of the synaptic vesicles in the nerve terminal fuse with the plasma membrane in response to each action potential. But for the nerve terminal to respond rapidly and repeatedly, the vesicles need to be replenished very quickly after they discharge. Thus, most synaptic vesicles are generated not from the Golgi membrane in the nerve cell body toàn thân but by local recycling from the plasma membrane in the nerve terminals. It is thought that the membrane components of the synaptic vesicles are initially delivered to the plasma membrane by the constitutive secretory pathway and then retrieved by endocytosis. But instead of fusing with endosomes, most of the endocytic vesicles immediately fill with transmitter to become synaptic vesicles.
The membrane components of a synaptic vesicle include carrier proteins specialized for the uptake of neurotransmitter from the cytosol, where the small-molecule neurotransmitters that mediate fast synaptic signaling are synthesized. Once filled with neurotransmitter, the vesicles return to the plasma membrane, where they wait until the cell is stimulated. After they have released their contents, their membrane components are retrieved in the same way and used again ().
Figure 13-64The formation of synaptic vesicles. These tiny uniform vesicles are found only in nerve cells and in some endocrine cells, where they store and secrete small-molecule neurotransmitters. The import of neurotransmitter directly into the small endocytic (more...)
Summary
Proteins can be secreted from cells by exocytosis in either a constitutive or a regulated fashion. In the regulated pathways, molecules are stored either in secretory vesicles or synaptic vesicles, which do not fuse with the plasma membrane to release their contents until an appropriate signal is received. Secretory vesicles bud from the trans Golgi network. The secretory proteins they contain condense during the formation and maturation of secretory vesicles. Synaptic vesicles, which are confined to nerve cells and some endocrine cells, form from endocytic vesicles and from endosomes, and they are responsible for the regulated secretion of small-molecule neurotransmitters. Whereas the regulated pathways operate only in specialized secretory cells, a constitutive secretory pathway operates in all eucaryotic cells, mediated by continual vesicular transport from the trans Golgi network to the plasma membrane.
Proteins are delivered from the trans Golgi network to the plasma membrane by the constitutive pathway unless they are diverted into other pathways or retained in the Golgi apparatus. In polarized cells, the transport pathways from the trans Golgi network to the plasma membrane operate selectively to ensure that different sets of membrane proteins, secreted proteins, and lipids are delivered to the different domains of the plasma membrane.
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