Insulin Signaling -- Movie Narrative

A biological individual consists of multiple organs with specialized functions. For the organism to function properly in its environment, these organs must communicate. This communication often involves a signal sent from one location to another that instructs the second organ about the status of some cellular feature. Glucose is a good example.

Glucose is a critical product of digestion. It is an essential energy source for cellular metabolism. This energy is produced when glucose is used as a substrate for glycolysis and then the Krebs or Citric Acid Cycle.

Following the digestion of food, higher levels of glucose circulate through the blood stream where it enters different cell types. In muscle cells glucose is readily used to produce energy and is also stored as glycogen, a secondary short term energy source. In fat cells, glucose is used for Triglyceride production, and acts as an important energy reserve molecule.

Here we will illustrate the signaling pathway that occurs when glucose is at high levels. This pathway involves multiple proteins and signaling events. This is termed cytoplasmic signaling. Different types of cells perform similar signaling steps in response to changes in their environment.

In the Protein Recycling Animation we see a group of storage vesicles enriched with GLUT4 proteins continuously recycling from the Cell Membrane to an inactive location in the cytosol. GLUT4 is a protein that facilitates the movement of glucose into the cell.

When high levels of glucose are detected by beta cells in the pancreas, insulin is released by the cells. The insulin circulates through the blood stream until it binds to an insulin receptor embedded in the cell membrane of a muscle, fat, or brain cell. Once the insulin binds to the receptor, phosphate groups are added to the intracellular domain of the receptor. Since the receptor itself adds the phosphate groups, the process is called autophosphorylation.

This phosphorylation event sets off a cascade of molecular events. The activated receptor protein then adds a phosphate group to another closely associated protein. This effectively passes the signal from the receptor to the next step in the signal pathway.

Proteins that add phosphate groups to another protein are called kinases. Kinases are often components of signal pathways, and phosphorylation is an important component in the transmission of a signal from one compartment to another. In this system, the signal corresponds to the level of blood glucose and is transmitted from outside to inside the cell.

Next we see a large pool of molecules that are embedded in the membrane also being phosphorylated. Other proteins are then in turn phosphorylated, further transmitting the first extracellular signal that was originally sent from outside the cell membrane.

So how does this affect the uptake of glucose? As we mentioned before, Glut4 is a glucose transporter, and Glut4 Storage Vesicles are held in a recycling state near the cell membrane. The vesicles are held mostly in this region because the RAB proteins that interact with the motor proteins necessary to move the vesicles to the membrane are in an inactive state.

The final step in the signal pathway involves the phosphorylation of a protein that prevents the RAB proteins from interacting with the vesicles.

When the RAB proteins are no longer inhibited, the storage vesicles can freely merge with the membrane. Once the vesicles have merged many Glut4 proteins are embedded in the membrane and large quantities of glucose can move into the cell. It is the signaling pathway that insures only the correct molecules will be allowed to enter the target cell.