Glucagon Mechanism of Action

Let's illustrate the mechanism of glucagon action.

• To do this, draw the membrane of a hepatic cell with a G-protein coupled receptor (GPCR) embedded within it.

• Now, draw adenylyl cyclase also in the membrane.

• Step 1: Show that glucagon binds the GPCR.

• Step 2: Indicate that this causes the alpha subunit to exchange GDP for GTP.
  • Show that the alpha subunit then activates adenylyl cyclase, which increases intracellular cAMP.

• Step 3: Show that cAMP activates protein kinase A.

• Step 4: Indicate that protein kinase A phosphorylates a number of downstream enzymes.
  • Show that this activates catabolic enzymes and inactivates anabolic enzymes.

• Specifically, indicate that the following processes are activated:

• Glycogen and lipid breakdown
• Gluconeogenesis

• Indicate that glycogen, protein and lipid synthesis, however, are inhibited.
  • Again, these actions oppose that of insulin, which promotes anabolic processes and glucose storage.

• Note that the other counterregulatory hormones control the same processes, but do so in response to other stimuli.
  • For example, epinephrine activates these pathways in response to physiologic stress.

• As an important point, indicate that our hepatocyte has G-protein coupled receptor's for both glucagon and epinephrine.

• Next, indicate that muscle cells only have receptors for epinephrine, not glucagon!

• To emphasize this point return to our table and denote that glucagon does not bind GPCR's in the muscle.

Now, we have covered the short-term responses of glucagon in a hepatocyte.

• What about the long-term responses?
  • Return to our diagram and write that much like insulin, glucagon has a long-term response at the transcriptional level: it produces an increase in the number of gluconeogenic enzymes over the course of hours/days.