Figure 13–64 The 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 Tgn; often the aggregates become more condensed as secretory vesicles mature and their lumen becomes more acidic. second, clathrincoated vesicles retrieve excess membrane and lumenal content present in immature secretory vesicles as the secretory vesicles mature. (b) This electron micrograph shows secretory vesicles forming from the Tgn in an insulin-secreting β cell of the pancreas. anti-clathrin antibodies conjugated to gold spheres (black dots) have been used to locate clathrin molecules. The immature secretory vesicles, which contain insulin precursor protein (proinsulin), contain clathrin patches, which are no longer seen on the mature secretory vesicle. (b, courtesy of lelio orci.) as well as many secreted hydrolytic enzymes, are synthesized as inactive precursors. Proteolysis is necessary to liberate the active molecules from these precursor proteins. The cleavages occur in the secretory vesicles and sometimes in the extracellular fluid after secretion. Additionally, many of the precursor proteins have an N-terminal pro-peptide that is cleaved off to yield the mature protein. These proteins are synthesized as pre-pro-proteins, the pre-peptide consisting of the ER signal peptide that is cleaved off earlier in the rough ER (see Figure 12–36). 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 13–66).
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: the delay prevents the protein 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 reach the site of secretion, which in some cells is far away from the TGN. Nerve cells are the most extreme example. Secretory proteins, such as peptide neurotransmitters (neuropeptides), which will be released from nerve terminals at the end of the axon, are made and packaged into secretory vesicles in the cell body. They 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 transport vesicles to the cell surface for constitutive exocytosis.
Whereas transport vesicles containing materials for constitutive release fuse with the plasma membrane once they arrive there, secretory vesicles in the regulated pathway wait at the membrane until the cell receives a signal to secrete, and they then fuse. The signal can be an electrical nerve impluse (an action potential) or an extracellular signal molecule, such as a hormone: in either case, it leads to a transient increase in the concentration of free Ca2+ in the cytosol.
for rapid exocytosis, synaptic vesicles are primed at the presynaptic plasma Membrane