6.3 Uncoupling and receptor recycling
Receptors that have been directed to the early endosome generally behave in one of two ways. They may return to the plasma membrane by vesicular transport or they may be transported to the lysosomes, where they are degraded. Rapid recycling of receptors in general occurs for receptors that bring ligand into the cell, whereas receptors involved in signal transduction are usually degraded. Note that these are generalisations and specific receptors may take different routes through the cell.
Two possible fates for a receptor–ligand complex in which the receptor may return to the plasma membrane are:
The receptor and ligand both recycle. The transferrin receptor provides the classic example of this pathway (see Figure 12). A transferrin receptor recycles every 15–20 minutes and has a half-life of about 30 hours.
The receptor recycles to the surface in coated vesicles while the ligand is degraded. This pathway is used by receptors that transport ligand into cells at high rates. A receptor recycles every 1–20 minutes and can undertake about 100 cycles during its lifetime of around 20 hours.
The classic example of this latter pathway is the LDL receptor, whose ligand is the plasma low-density lipoprotein apolipoproteins E and B (collectively known as LDLs). For example, Apo-B is a large protein (Mr ~ 500,000) that carries cholesterol and cholesterol esters. The LDL is released from its receptor in the endosome and the receptor recycles to the surface to be used again. The LDL, having released cholesterol for use by the cell, is sent on to the lysosomes, where it is degraded. This represents the major route for removing cholesterol from the circulation, and people with mutations in the gene encoding the LDL receptor accumulate large amounts of plasma cholesterol, which causes the disease known as familial hypercholesterolemia. In fact, characterisation of the internalisation defect provided evidence that entry into coated pits is needed for receptor-mediated endocytosis of LDL. In cells from human patients with such defects in the LDL receptor, the receptors gather in small clusters over the plasma membrane and cannot enter the coated pits. The mutations responsible for this type of defect all affect the cytoplasmic domain of the receptor that mediates endocytosis.
Two possible fates for a receptor–ligand complex in which the receptor does not return to the plasma membrane are:
The receptor and ligand are both degraded. The epidermal growth factor (EGF) receptor binds its ligand (a small polypeptide), and is internalised. Although EGF and its receptor appear to dissociate at low pH, they are both carried to the lysosomes, where they are degraded (see Figure 12).
The receptor and ligand are transported elsewhere. This pathway is seen in some polarised cells in which the receptor–ligand complex is taken up at one cell surface, and then released at another (e.g. the transport of IgA, see Figure 14). Other pathways have been described for specific receptors, including recycling between the cell membrane, endosomes and the Golgi network.