13.2 Glucagon and epinephrine

The metabolic effects of glucagon and epinephrine are similar to each other but opposite to that of insulin. Glucagon is mainly concerned with metabolic regulation, whereas epinephrine also has pronounced effects on heart rate, blood pressure and so on. While the two hormones have separate, specific receptors, both of these fall into the group of the G protein-coupled receptors (GPCRs).

The workings of a GPCR are illustrated in Figure 13.1.3-3. The receptor is a membrane protein with seven transmembrane helices, which on its cytosolic face is associated with a GTP-binding protein, or G protein. This protein has three subunits; the α-subunit is bound to GDP in its resting state. Signal transduction by a GPCR works as follows:

Binding of the ligand to the extracellular face of the receptor causes a conformational change that involves both the receptor and the G protein.
On the G protein, the conformational change leads to the exchange of GDP for GTP on the α-subunit.
Upon binding of GTP, the α-subunit dissociates from the βγ-dimer and binds to its effector protein.
After a certain amount of time, the GTPase activity that is built into the α-subunit cleaves GTP to GDP.
Cleavage of GTP causes the α-subunit to revert to its inactive conformation, to leave its target protein, and to re-associate with the βγ-dimers. The system thus returns to its resting state.

Both the epinephrine receptor¹ and the glucagon receptor are coupled to the same G protein, which binds to adenylate cyclase as its effector protein and activates it. Because of this, the metabolic effects on a cell that has receptors for both of them will always be similar. Differences between the effects of the two hormones arise from the fact that the receptors have different tissue distributions; many cells have receptors for epinephrine but not glucagon.

The consequences of the stimulation of adenylate cyclase are depicted in Figure 13.2-1. Protein kinase A, as we have seen before, has several effects:

It phosphorylates and thereby inactives glycogen synthase.
It also phosphorylates phosphorylase kinase, which in turn phosphorylates and thereby activates glycogen phosphorylase, so that more glucose gets released from glycogen.
It phosporylates phosphofructokinase 2, thereby switching on the fructose-2,6-bisphosphatase activity on that bifunctional enzyme. This reduces the concentration of fructose-2,6-bisphosphate and slows down glycolysis and accelerates gluconeogenesis.
It phosphorylates and thereby activates hormone-sensitive lipase in fat tissue. This leads to the release of glycerol and fatty acids into the blood.

As stated before, all these effects are antagonistic to those of insulin and will tend to sustain or increase blood glucose levels.

1: More specifically, the β-adrenergic receptor, of which there again are several subtypes.