In all eukaryotic cells, proteins that are destined for the plasma membrane or secretion are synthesised in the rough endoplasmic reticulum and enter the Golgi apparatus where they undergo a variety of post-translational modifications, before transfer to the cell surface in secretory vesicles.
Which post-translational modifications of proteins occur in which compartment?
N-glycosylation and N-myristoylation occur in the ER. Remodelling of N-glycosyl residues and O-glycosylation occur in the Golgi network. Sulfation takes place in the trans Golgi network (Section 3).
The processes of exocytosis are closely related to those used for importing molecules into the cell. But secretory vesicles not only transport molecules to the plasma membrane, they also provide a mechanism for replenishing and remodelling the plasma membrane with lipids and proteins. The addition of membrane lipids by exocytosis balances the loss of membrane that occurs during endocytosis. Also, membranes in every cell need to be replenished continuously as they become ‘aged’.
When introducing the subject of secretion we made a distinction between constitutive and regulated exocytosis or secretion. Based on your understanding of this distinction, say which of the following are constitutive and which are regulated.
Release of the hormone adrenalin from cells in the adrenal medulla.
Release of the neurotransmitter acetylcholine at the motor end-plate (nerve/muscle junction).
Release of the proteolytic enzyme pepsin from gastric epithelium.
Release of the cytokine receptor IL-4 to the surface of B cells.
Release of the inflammatory mediator serotonin from granules in mast cells.
Release of collagen from fibroblasts to form the extracellular matrix.
They are all examples of regulated secretion except for numbers 4 and 6. Hormones, neurotransmitters, the proteolytic enzymes in the gut and mediators are all secreted at relatively short notice in response to an external stimulus. The release of the IL-4 receptor to the plasma membrane occurs in response to activation of the B cell but is regulated at the level of mRNA transcription; likewise collagen production by fibroblasts. In the case of unregulated secretion, the cell is producing molecules that affect itself or its immediate environment.
In this section we are going to look in detail at one example of regulated secretion, the secretion and release of neurotransmitter from synaptic vesicles, and the way in which this process is triggered. We have already looked at the way in which a synaptic vesicle is coated, and at some of the molecules, such as syntaxin and synaptobrevin, that target it to active zones in the plasma membrane, and effect recovery of the vesicle components. Here we shall continue studying the release of neurotransmitters, but focus on how their release is triggered.
While many neurotransmitters are small molecules (e.g. dopamine and acetylcholine), and are synthesised at the nerve terminal, some are polypeptides, which are synthesised in the rough ER and modified in the Golgi apparatus. However, most neuroactive peptides are not synthesised in the form in which they are eventually secreted, but as a part of a larger inactive precursor protein, or prohormone. Proteolysis of the precursor into smaller fragments, including the active peptides, occurs in the secretory vesicles and in the Golgi apparatus. In some cases, several different neuroactive peptides may be generated from a single precursor. It is possible that there is some advantage in producing small peptides from a large precursor molecule, because such peptides may be too small to carry the necessary signal sequences to send them to their destination; the precursor contains the signals for translation, Golgi processing and intracellular localisation, and the final peptides are released only when all these steps have been completed.
After synthesis near the body of the neuron, neuroactive peptides are packed into the vesicles and transported along microtubules in the axon to the release sites, where they are stored until an appropriate stimulus arrives. The distance from the site of synthesis to the point of use at the end of the nerve axon may be considerable. Note that this mechanism to resupply the nerve terminal with neuropeptides and transmitters is a long-term process, distinct from the rapid recycling and reformation of vesicles described in Figure 26.