32. Epinephrine and glucagon

Last updated on November 19, 2018 at 17:16

Summary

  • They act through the same pathways, but epinephrine mostly targets muscle while glucagon mostly targets the liver
  • Epinephrine binds to adrenergic receptors, while glucagon binds to glucagon receptor
  • Both receptors are G-protein coupled receptors, which activate adenylyl cyclase, which increases cellular level of cAMP, which activates PKA, which mediates the cellular response.
  • The main effect of glucagon is to limit the glucose consumption of the liver and instead increase blood glucose through gluconeogenesis
  • The main effect of epinephrine is to increase the glycolysis and glycogenolysis in mucle
  • PKA inhibits cholesterol synthesis, glycogen synthesis and fatty acid synthesis. It also inhibits glycolysis in liver, but activates it in muscle.
  • PKA activates glycogen breakdown and gluconeogenesis.
  • The β-adrenergic receptor is desensitized after binding epinephrine, by the effect of βARK and β-arrestin

The pathway

The epinephrine and glucagon receptors are G-protein coupled receptors. When their ligand binds to them, the receptor binds a GTP, which activates it. This activation causes the receptor to move to a nearby, membrane-bound enzyme called adenlylyl cyclase. This enzyme catalyses the reaction of converting ATP to cAMP. When the level of cAMP in the cell increases, a protein called Protein Kinase A is activated. PKA is what mediates the cells response. It’s a kinase, a protein that can phosphorylate.

PKA then phosphorylates many different enzymes, to either increase or decrease their activity, depending on the enzyme. Remember that epinephrine and glucagon are hormones that signal for the body to raise the blood glucose level, while decreasing the amount of glucose the liver uses. With this is mind, it’s easier to remember what PKA affect. PKA activates enzyme related to gluconeogenesis, β-oxidation and glycogen breakdown, while inhibiting enzymes that are related to pathways that use energy for other things than gluconeogenesis, like cholesterol synthesis, fatty acid synthesis and glycogen synthesis.

There’s only one difference in the effect of glucagon and epinephrine. Epinephrine acts on both the liver and muscle, but glucagon only on the liver. Both hormones inhibit glycolysis in the liver, to prevent the liver from using unnecessary glucose, but epinephrine also increases glycolysis in muscle.

After a while, the enzyme called cyclic nucleotide phosphodiesterase or simply PDE, will degrade cAMP to 5’-AMP, which will decrease the level of cAMP in the cell, which will reverse the effects of the hormone.

This figure summarizes the pathway of glucagon and epinephrine. More details can be found here. Epinephrine’s pathway is identical to glucagons except for the fact that in muscle, PFK2 and FBPhase-2 are not regulated by PKA at all.

Desensitization of the β-adrenergic receptor

One type of adrenergic (epinephrine) receptor is the β-adrenergic receptor. This receptor can be desensitized, which means that the cell becomes less sensitive to the hormone. After the receptor has bound an epinephrine, a protein called βARK will phosphorylate the receptor, which inactivates it. Following this, another protein called β-arrestin, or βarr, will bind to the phosphorylated receptor, and remove the whole receptor from the cell surface by endocytosis. As the receptor isn’t on the surface anymore, but in a vesicle inside the cell, it obviously can’t bind epinephrine anymore.

After a period, βarr dissociates, and the receptor is returned to the cell surface.

Synthesis of epinephrine and glucagon

The synthesis of the catecholamines. Note that ascorbate is vitamin C

Glucagon is synthesized in the Langerhans islets in the pancreas, by α-cells. It’s a peptide hormone.

Epinephrine is synthesized from tyrosine. This synthesis needs vitamin C (ascorbate), adoMet, THB and PLP.

Below is a table with some enzymes that PKA, and therefore epinephrine and glucagon, affects

Name of enzyme Activated or inhibited? Belonging to which pathway?
HMG-CoA reductase Inhibited Cholesterol synthesis
Acetyl-CoA carboxylase Inhibited Fatty acid synthesis
Pyruvate kinase (liver) Inhibited Glycolysis
Phosphofructokinase-2 Inhibited Activates glycolysis
Glycogen phosphorylase kinase Activated Activates glycogen phosphorylase
Fructose 2,6-bisphosphatase Activated Inhibits glycolysis

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31. Hormones

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33. Insulin

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