32. Epinephrine and glucagon

Last updated on March 13, 2020 at 13:05

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

Glucagon

Glucagon is a hormone which is produced by alpha cells in the Langerhans islets of the pancreas. The purpose of the hormone is to increase the level of glucose in the blood between meals.

Right after a meal the blood glucose level is high, as the carbohydrates from the meal are converted to glucose and transported into the blood. Some time after the meal the blood glucose level decreases as the tissues of the body consume the glucose for energy, and/or store the glucose as fat, protein or glycogen.

The blood glucose level should always be kept above approximately 4,0 mmol/L. When the blood glucose level sinks to this level, the pancreas will start to produce more and more glucagon. Glucagon signals to the liver that it should perform gluconeogenesis and glycogenolysis, and that the liver should stop glycolysis. Gluconeogenesis and glycogenolysis both yield glucose, which maintains the blood glucose level within normal range.

Epinephrine

Epinephrine, also called adrenaline, is a hormone which is produced by cells of the medulla of the adrenal gland. The purpose of this hormone is to prepare the body to periods of stress, as part of the “fight or flight” response. The biochemical purpose of the hormone is to increase the level of glucose in the blood during periods of stress. Whether choosing to fight or to flee, the skeletal muscles require a lot of energy in the form of blood glucose. The hormone also has many other effects on the body, like stimulating the heart, inhibiting peristalsis in the GI tract, increasing blood pressure, etc., but those functions are more relevant in physiology.

The synthesis of epinephrine is stimulated by sympathetic activation, which occurs during stress. Epinephrine will then travel to the liver, where it will bind to (β2)-adrenergic receptors. This will stimulate glycogenolysis, which increases the blood glucose level. Epinephrine will also act on other tissues:

  • It will bind to (β2)-adrenergic receptors on skeletal muscles, stimulating glycogenolysis
    • This yields glucose for the muscles
  • It will bind to (β2)-adrenergic receptors on adipose tissue, stimulating lipolysis
    • This yields fatty acids for the muscles

The pathway

There are four types of adrenergic receptor, each with different signal transduction. However, only the β2 adrenergic receptors are relevant for biochemistry, so we’ll only care about that subtype now.

Glucagon receptor and the adrenergic receptors are G-protein coupled receptors. When the hormone binds to them, the receptor binds activates the 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.

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 glucagon’s except for the fact that in muscle, PFK2 and FBPhase-2 are not regulated by PKA at all.

Desensitization of the β-adrenergic receptor

The β-adrenergic receptor can be desensitized, which means that the cell becomes less sensitive to the hormone after being exposed to the hormone for a long time. 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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