33. Epinephrine and glucagon

Learning objectives

• What is the purpose of glucagon, and where is it synthesised?
• In which physiological state is glucagon released?
• Describe the synthesis of epinephrine
• In which physiological state is epinephrine released?
• Glucagon and epinephrine act by which signalling pathway?
• Describe the PKA pathway from hormone-receptor binding to the activation of PKA
• What are the differences in the biochemical actions of glucagon and epinephrine?
• Which biochemical processes are stimulated by PKA?
• Which biochemical processes are inhibited by PKA?
• Describe the desensitization of the β-adrenergic receptor

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.

Function

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 toward 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.

Synthesis

Epinephrine is synthesized from tyrosine, like this:

Tyrosine -> L-DOPA -> Dopamine -> Norepinephrine -> Epinephrine

This synthesis needs vitamin C (ascorbate), adoMet, THB and PLP.

Function

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

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

The PKA pathway

The PKA pathway

Main article: Protein kinase A pathway

Both glucagon and epinephrine increase gluconeogenesis and glycogenolysis, and they inhibit the utilization of glucose by the liver. The two hormones achieve theses similar effects by acting through very similar pathways.

Differences between glucagon and epinephrine pathways

Glucagon acts only on the liver, while epinephrine acts on muscle, liver, as well as other tissues.

Notably, PKA inhibits L-type pyruvate kinase (which is in the liver) but does not influence pyruvate kinase in the muscle. This causes glucagon and epinephrine to inhibit glycolysis in the liver.

From receptor binding to PKA activation

Both glucagon receptor and the β2-adrenergic receptor 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.

After PKA activation

PKA then phosphorylates many different enzymes. This either increases or decreases 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.

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 decrease the effect of PKA, eventually reversing the effects of the hormone.

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 rather inside a vesicle inside the cell, it obviously can’t bind epinephrine anymore. The receptor is now desensitized.

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

Summary

• What is the purpose of glucagon, and where is it synthesised?
  • Glucagon upholds the blood glucose level in periods of fasting
  • It’s synthesised by alpha cells in the Langerhans islets
• In which physiological state is glucagon released?
  • Glucagon is released during fasting
• Describe the synthesis of epinephrine
  • Tyrosine -> L-DOPA -> Dopamine -> Norepinephrine -> Epinephrine
  • Needs vitamin C, adoMet, THB and PLP.
• In which physiological state is epinephrine released?
  • During periods of stress
• Glucagon and epinephrine act by which signalling pathway?
  • The protein kinase A pathway
• Describe the PKA pathway from hormone-receptor binding to the activation of PKA
  • Glucagon binds to glucagon receptor or epinephrine binds to β-adrenergic receptor, both of which are G-protein coupled receptors
  • This stimulates adenylyl cyclase, which synthesises cAMP
  • cAMP activates PKA
• What are the differences in the biochemical actions of glucagon and epinephrine?
  • Glucagon acts only on the liver, while epinephrine acts on muscle, liver, as well as other tissues.
  • Both inhibit L-type pyruvate kinase in the liver, thereby inhibiting glycolysis there
• Which biochemical processes are stimulated by PKA?
  • Triacylglycerol breakdown
  • Glycogenolysis
  • Gluconeogenesis
• Which biochemical processes are inhibited by PKA?
  • Glycogen synthesis
  • Cholesterol synthesis
  • Fatty acid synthesis
• Describe the desensitization of the β-adrenergic receptor
  • βARK phosphorylates the receptor, and βarr removes it from the cell surface by endocytosis