7.3 Regulation of secretion
Up to this point we have made a clear distinction between constitutive secretion and regulated secretion. In reality however the border is a bit more blurred. For example, many molecules are constitutively expressed on the surface of a cell, but their expression is increased in response to a particular stimulus. In other words, surface expression is determined by both constitutive and regulated secretion. Constitutive secretion is regulated primarily at the level of protein synthesis, whereas regulated secretion is controlled at the level of release from intracellular stores.
What is the essential functional difference for the cell in regulating the surface expression of molecules by one mechanism or the other? Think in terms of how long it takes a cell to respond.
If a cell responds to a stimulus by changing its level of protein synthesis, it will take time before any change is seen in the level of expression at the cell surface (>2 h). But if it responds by releasing molecules from intracellular stores (secretory vesicles), the level of expression on the plasma membrane will increase within seconds.
For this reason, cells that need to respond quickly to a stimulus often retain intracellular stores of molecules that can be rapidly mobilised to the cell surface. In this section, we are going to look briefly at a group of cell surface proteins called selectins, which are regulated in this way. Selectins play important roles in blood clotting and in leukocyte migration from the blood into tissues.
Selectins are expressed on the plasma membrane of blood platelets and endothelial cells lining blood vessels as well as on leukocytes. They mediate cell-to-cell adhesion. All selectins carry an extracellular lectin domain, which allows them to interact with polymeric carbohydrates present on glycoproteins of other cells. There are three members of the selectin family, E-selectin (Endothelial), P-selectin (Platelet) and L-selectin (Leukocyte) (Figure 45), named according to the cells that express them. In practice however, expression of each selectin is not confined to just one cell type, for example both E-selectin and P-selectin are expressed on blood vessel endothelium. The function of P-selectin on endothelium is principally concerned with blood clotting, and the function of E-selectin with leukocyte migration into tissue – a component of inflammation. When an endothelial cell is activated by a suitable stimulus, the surface expression of P-selectin increases within minutes, and the expression of E-selectin increases over 2–8 h.
Which of these two selectins is regulated at the level of protein synthesis and which by regulated secretion? Can you relate the way the cell controls the expression of its selectins to their physiological functions?
E-selectin expression is enhanced by increasing protein synthesis, which takes several hours, and inflammation is a process that develops over a period of hours or days. P-selectin expression is rapidly increased by release from intracellular stores: blood clotting is, of necessity, a speedy response.
There are numerous other examples of proteins whose expression is controlled by both constitutive production and regulated secretion. Moreover, even a protein such as insulin, whose release is controlled by regulated secretion, must be replenished by an appropriate level of protein synthesis.